Individual X

Legend

Annovar Function	Annovar: Function prediction
Annovar Mutation type	Annovar: Mutation type prediction
Annovar Region type	Annovar: Region type prediction
ccdsGene name	Consensus Coding Sequence Database (CCDS): gene name
CosmicCodingMuts gene	Catalogue of Somatic Mutations in Cancer (COSMIC): gene name
cytoBand name	Cytoband location of gene
dbNSFP KGp1 AF	dbNSFP: Alternative allele frequency in the whole 1000Gp1 data.
dbNSFP KGp1 Afr AF	dbNSFP: Alternative allele frequency in the 1000Gp1 African descendent samples.
dbNSFP KGp1 Amr AF	dbNSFP: Alternative allele frequency in the 1000Gp1 American descendent samples.
dbNSFP KGp1 Asn AF	dbNSFP: Alternative allele frequency in the 1000Gp1 Asian descendent samples.
dbNSFP KGp1 Eur AF	dbNSFP: Alternative allele frequency in the 1000Gp1 European descendent samples.
dbNSFP LR score	dbNSFP: logistic regression (LR) based ensemble prediction score, which incorporated 10 scores (SIFT, PolyPhen-2 HDIV, PolyPhen-2 HVAR, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy, PhyloP) and the maximum frequency observed in the 1000 genomes populations. Larger value means the SNV is more likely to be damaging. The threshold seperationg 'T(olerated)' and 'D(amaging)' is 0.5.
dbNSFP Uniprot Acc	dbNSFP: Uniprot accession number
dbNSFP Uniprot ID	dbNSFP: Uniprot ID number
dbSNP Clinical Significance	dbSNP: Variant Clinical Significance, 0 - unknown, 1 - untested, 2 - non-pathogenic, 3 - probable-non-pathogenic, 4 - probable-pathogenic, 5 - pathogenic, 6 - drug-response, 7 - histocompatibility, 255 - other
dbSNP GMAF	dbSNP: Global Minor Allele Frequency [0, 0.5]; global population is 1000Gp1
dbSNP name	dbSNP: rsID
EntrezGene Description	Entrez Gene: Description (a descriptive name for this gene)
EntrezGene GeneID	Entrez Gene: ID (unique identifier for a gene)
EntrezGene Symbol	Entrez Gene: Symbol (default symbol for the gene)
EntrezGene Type of gene	Entrez Gene: Type, given by http://www.ncbi.nlm.nih.gov/IEB/ToolBox/CPP_DOC/lxr/source/src/objects/entrezgene/entrezgene.asn
ESP Afr MAF	NHLBI GO Exome Sequencing Project (ESP): The African American minor-allele frequency in percent.
ESP All MAF	NHLBI GO Exome Sequencing Project (ESP): The minor-allele frequency in percent for all populations.
ESP ClinicalLink	NHLBI GO Exome Sequencing Project (ESP): The potential clinical implications associated with a SNP
ESP Eur/Amr MAF	NHLBI GO Exome Sequencing Project (ESP): The European American minor-allele frequency in percent.
ExAC AF	Exome Aggregation Consortium (ExAC): Alternate Allele Freq
gene	refGene: gene name
OMIM Clinical Significance	Online Mendelian Inheritance in Man (OMIM): Clinical Significance
OMIM Description	Online Mendelian Inheritance in Man (OMIM): Description
OMIM Title	Online Mendelian Inheritance in Man (OMIM): Title
snpEff Effect	snpEff: predicted highest-impact effect resulting from the current variant (or one of the highest-impact effects, if there is a tie)
snpEff Functional Class	snpEff: predicted functional class of the highest-impact effect resulting from the current variant (none, silent, missense, or nonsense)
snpEff Gene Biotype	snpEff: predicted gene biotype for the highest-impact effect resulting from the current variant
snpEff Gene Name	snpEff: Gene name prediction
snpEff Impact	snpEff: predicted impact of the highest-impact effect resulting from the current variant (high, moderate, low, or modifier)

FAM87B

dbSNP name	rs3131967(T,C); rs3115859(G,A)
cytoBand name	1p36.33
EntrezGene GeneID	400728
EntrezGene Description	family with sequence similarity 87, member B
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	transcript
snpEff Functional Class	none
snpEff Gene Biotype	lincRNA
snpEff Impact	modifier
dbSNP GMAF	0.3168

LINC00115

dbSNP name	rs2286139(C,T)
cytoBand name	1p36.33
EntrezGene GeneID	79854
snpEff Gene Name	NCRNA00115
EntrezGene Description	long intergenic non-protein coding RNA 115
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	transcript
snpEff Functional Class	none
snpEff Gene Biotype	lincRNA
snpEff Impact	modifier
dbSNP GMAF	0.3875

TNFRSF4

dbSNP name	rs17568(C,T)
ccdsGene name	CCDS11.1
cytoBand name	1p36.33
EntrezGene GeneID	7293
EntrezGene Description	tumor necrosis factor receptor superfamily, member 4
EntrezGene Type of gene	protein-coding
Annovar Function	TNFRSF4:NM_003327:exon5:c.G534A:p.E178E,
Annovar Mutation type	synonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.0
snpEff Effect	synonymous_coding
snpEff Functional Class	silent
snpEff Gene Biotype	protein_coding
snpEff Impact	low
dbNSFP KGp1 AF	0.45467032967
dbNSFP KGp1 Afr AF	0.469512195122
dbNSFP KGp1 Amr AF	0.475138121547
dbNSFP KGp1 Asn AF	0.756993006993
dbNSFP KGp1 Eur AF	0.207124010554
dbSNP GMAF	0.4559
ESP Afr MAF	0.379452
ESP All MAF	0.264224
ESP Eur/Amr MAF	0.205236
ExAC AF	0.354

*OMIM Information*

OMIM Clinical Significance

Cardiac:
Atrioventricular septal defect (AVSD);
Ostium primum atrial septal defect;
Ventricular septum inlet defect;
Tricuspid and mitral valves are replaced by a single inlet valve;
Congestive failure;
Lower left sternal thrill and pansystolic murmur;
Poorly localized midsystolic murmur

Skin:
Cyanosis

Lung:
Pulmonary hypertension

Misc:
Characteristic feature of Down syndrome

Lab:
Superior axis and first-degree heart block on EKG;
Chararacteristic 4-chamber echocardiogram

Inheritance:
Autosomal dominant with variable expression and incomplete penetrance

OMIM Title
*600315 TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 4; TNFRSF4
;;TAX-TRANSCRIPTIONALLY ACTIVATED GLYCOPROTEIN 1 RECEPTOR; TXGP1L;;
OX40 ANTIGEN;;
LYMPHOID ACTIVATION ANTIGEN ACT35; ACT35;;
CD134

OMIM Description

DESCRIPTION

TNFRSF4 encodes a transmembrane protein belonging to the TNF receptor
superfamily (see 191190). The TNFRSF4 protein is a costimulatory
molecule implicated in long-term T-cell immunity (summary by Byun et
al., 2013).

CLONING

The ACT35 antigen is a cell surface glycoprotein that was discovered
through the production of a monoclonal antibody raised against the
HUT-102 cell line. Its expression can be induced on lymphocytes by
mitogen stimulation or viral stimulation. Because the cell and tissue
distribution resembles the pattern of the IL2 receptor, CD25 (147730),
it was speculated that a relationship between the ACT35 antigen and the
CD25 antigen exists. Latza et al. (1994) cloned a cDNA for the ACT35
antigen and showed its strong homology with the previously described rat
OX40 antigen. It is therefore another member of the tumor necrosis
factor/nerve growth factor receptor family. Birkeland et al. (1995)
cloned cDNA and genomic DNA for the mouse homolog.

Byun et al. (2013) reported that the 277-amino acid human OX40 protein
contains an N-terminal signal peptide, followed by 4 cysteine-rich
domains, a transmembrane domain, and a C-terminal cytosolic domain.

GENE STRUCTURE

Birkeland et al. (1995) determined the gene structure of mouse OX40,
which showed that there are several intron/exon bodies shared between
OX40 and CD27 (186711), CD40 (109535), TNFR1 (191190), and CD95
(134637).

MAPPING

By fluorescence in situ hybridization, Latza et al. (1994) mapped the
ACT35 gene to 1p36, where the genes for TNFR2 (191191) and the lymphoid
activation antigen CD30 (153243) are located.

Gross (2014) mapped the TNFRSF4 gene to chromosome 1p36.33 based on an
alignment of the TNFRSF4 sequence (GenBank GENBANK BC105070) with the
genomic sequence (GRCh37).

Birkeland et al. (1995) mapped the gene encoding murine OX40 to
chromosome 4 in an area that contains the gene for TNFR2 and shows
homology of synteny with the region of human chromosome 1 that contains
the genes for TNFR2, OX40, and CD30.

GENE FUNCTION

Song et al. (2004) showed that OX40 engagement sustains activation of
protein kinase B (PKB; 164730) and intermediates of PKB signaling
pathways, including PI3K (see 601232), GSK3 (see 606784), and FKHR
(FOXO1A; 136533). T cells from mice lacking Ox40 were unable to maintain
PKB activity over time, and this loss of activity coincided with cell
death. Expression of active PKB in responding Ox40 -/- cells reversed
the survival defect. Song et al. (2004) concluded that the duration of
signaling needed for long-term survival is much longer than that needed
for proliferation.

Munks et al. (2004) found that stimulation of 4-1BB (TNFRSF9; 602250) in
mice at the time of a DNA prime, poxvirus vaccine, increased the number
of functional memory CD8 (see 186910) T cells that responded, while
stimulation of OX40 increased the number of antigen-specific CD4
(186940) T cells that responded. Stimulating both of these TNFRs
enhanced the CD8 response more than stimulating 4-1BB alone. Munks et
al. (2004) suggested that stimulating these receptors can improve the
response to a powerful virus vector and may be useful in vaccine
development.

BIOCHEMICAL FEATURES

Using a single dose of agonistic antibody against OX40, Bansal-Pakala et
al. (2001) were able to prevent tolerance induction and to break
existing tolerance or augment the reactivity of hyporesponsive T cells.
Bansal-Pakala et al. (2001) proposed that targeting OX40 and possibly
other members of the TNFR family might have benefits as adjuvants.

MOLECULAR GENETICS

Byun et al. (2013) studied a 19-year-old Turkish woman with a primary
immunodeficiency (IMD16; 615593) presenting as childhood-onset classic
Kaposi sarcoma who had previously been reported as Case 3 by Sahin et
al. (2010). Homozygosity mapping and whole-exome sequencing identified a
homozygous arg65-to-cys (R65C; 600315.0001) mutation in the OX40 gene.
The patient's consanguineous parents, a younger sister, and a younger
brother were all heterozygous for R65C and HHV-8 seropositive, but they
were free of Kaposi sarcoma. Byun et al. (2013) noted that the
immunologic phenotype of the patient largely overlapped with that of
mice lacking Ox40. Flow cytometric analysis demonstrated that OX40 with
the R65C mutation was poorly expressed on T cells. Immunoblot analysis
of activated control T cells showed expression of a 50-kD OX40 protein,
with a minor fraction of 35 kD. However, in R65C heterozygotes and the
homozygous patient, the 35-kD form, which was associated with immature
carbohydrates and was exclusively intracellular, was predominant. The
patient's T cells were unable to bind or respond to OX40L, indicating
complete functional OX40 deficiency. All family members had a history of
BCG vaccination, but only the patient's T cells failed to respond to
tuberculin stimulation with IFNG (147570) production. Although
seropositive for a number of recall antigens, the patient did not make a
T-cell response to these antigens. Byun et al. (2013) proposed that the
patient's high susceptibility to Kaposi sarcoma may have resulted from
an inability to interact with OX40L, which is highly expressed on
HHV-8-infected endothelial cells.

ANIMAL MODEL

Using Ox40 -/- mice and a mouse model of asthma, Jember et al. (2001)
found that wildtype mice had significantly higher eosinophilic
infiltrate in the bronchial fluid than did Ox40 -/- mice. The
Ox40-deficient mice also had significantly reduced levels of the Th2
cytokines IL4 (147780) and IL5 (147850), but no elevation in IFNG
(147570), in bronchial fluid, and antigen-specific and total IgE was
reduced in serum. Functional analysis indicated that wildtype mice had
pronounced airway hyperreactivity compared with Ox40 -/- mice.
Histologic analysis revealed marked cellular infiltrate around the
bronchioles of wildtype mice and a near absence of mucus production by
Ox40 -/- mice. Jember et al. (2001) concluded that OX40/OX40L
interactions are integral to the development of the asthmatic phenotype.
They proposed that strategies targeting both OX40 and CD28 (186760) may
be most effective in preventing the development of allergen-specific T
cells.

OX40 is not expressed on naive T cells, but it is upregulated within 2
days of antigen activation. Humphreys et al. (2003) showed that
influenza virus-induced weight loss and T-cell inflammation in mice
could be reduced by an Ox40-Ig fusion protein. Flow cytometric and
intracellular cytokine analysis demonstrated that the number and
proportion of Cd8-positive T cells producing Tnf were reduced in treated
mice. Delayed treatment also inhibited weight loss in mice with
established illness without affecting viral clearance or antigen recall
responses. Reduced proliferation and enhanced apoptosis of lung cells
accompanied the improved clinical phenotype. Humphreys et al. (2003)
concluded that interference with the late costimulatory pathway has
potential for the treatment of dysregulated immune responses in lung.

Shimojima et al. (2004) found that CD134 is the primary receptor for
feline immunodeficiency virus. CD134 expression promotes viral binding
and renders cells permissive for viral entry, productive infection, and
syncytium formation. Infection is CXCR4 (162643)-dependent, analogous to
infection with X4 strains of HIV.

B3GALT6

dbSNP name	rs144527217(T,G); rs45578847(G,A); rs45591840(G,T); rs56852924(G,A); rs114208940(C,T); rs61353980(C,T)
cytoBand name	1p36.33
EntrezGene GeneID	126792
snpEff Gene Name	SDF4
EntrezGene Description	UDP-Gal:betaGal beta 1,3-galactosyltransferase polypeptide 6
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	upstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.004132

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Scapular winging (in some patients)

SKELETAL:
[Spine];
Hyperlordosis (in some patients);
[Pelvis];
Hip dysplasia (in some patients);
Hip contractures (in some patients);
[Limbs];
Knee contractures (in some patients);
[Feet];
Foot deformities;
Pes equinovarus;
Achilles tendon contractures

MUSCLE, SOFT TISSUE:
Muscle weakness, proximal and distal (predominant lower limb involvement);
Muscle atrophy, proximal and distal (predominant lower limb involvement);
Gower sign;
Axial muscle weakness;
Fasciculations (in some patients);
Neurogenic abnormalities seen on EMG;
Groups of atrophic fibers seen on muscle biopsy (type I fiber predominance)

NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Waddling gait;
Difficulty running;
Toe-walking;
Spasticity (in some patients);
Hyperreflexia (in some patients);
Upper motor signs (in some patients);
Loss of motor neurons in the anterior horn of the spinal cord;
[Peripheral nervous system];
Hyporeflexia, distal;
Areflexia, distal

MISCELLANEOUS:
Onset in early first decade, although some patients have onset at
birth or early in infancy;
Variable severity;
Slowly or non-progressive

MOLECULAR BASIS:
Caused by mutation in the homolog of the Drosophila bicaudal D, 2
gene (BICD2, 609797.0001)

OMIM Title
*615291 UDP-GAL:BETA-GAL BETA-1,3-GALACTOSYLTRANSFERASE POLYPEPTIDE 6; B3GALT6
;;GALACTOSYLTRANSFERASE II; GALTII;;
BETA-1,3-GALACTOSYLTRANSFERASE 6;;
BETA-3-GALT6

OMIM Description

DESCRIPTION

Glycosaminoglycan biosynthesis initiates with the formation of a linkage
tetrasaccharide that serves as a primer, followed by sequential transfer
of monosaccharide residues from the corresponding nucleotide sugars
starting at the reducing end. B3GALNT6 (EC 2.4.1.134) forms a galactose
(Gal)-beta-1,3-Gal linkage via the transfer of Gal from UDP-Gal to a
terminal beta-linked Gal residue and functions in the synthesis of
heparan sulfate and chondroitin sulfate (Bai et al., 2001).

CLONING

By searching an EST database for sequences similar to mouse
beta-1,3-galactosyltransferases (see B3GALT1, 603093), followed by
screening a human fetal brain cDNA library and a newborn mouse brain
cDNA library, Bai et al. (2001) cloned human and mouse B3GALT6, which
they designated GALTII. The deduced human and mouse proteins contain 329
and 325 amino acids, respectively. GALTII is a typical type II
transmembrane protein, with a transmembrane domain near the N terminus
and a C-terminal galactosyltransferase domain containing a conserved
cysteine residue. Northern blot analysis detected variable expression of
transcripts of about 1.6, 2.4, and 3.3 kb in all 16 human tissues
examined. Fluorescence-tagged GALTII colocalized with alpha-mannosidase
II (MAN2A1; 154582), a marker of the medial Golgi. Bai et al. (2001)
noted that the sequence and expression pattern of B3GALT6 had
erroneously been reported as that of B3GNT2 (605581) in a previous
publication (Zhou et al., 1999) due to a clerical error. The correct
B3GNT2 sequence and expression pattern were provided in an erratum.

GENE FUNCTION

Bai et al. (2001) found that human GALTII expressed in insect cells
showed strict requirement for UDP-Gal as a Gal donor. For a substrate,
it reacted strongly with Gal-beta-1,4-xylosyl-beta-O-benzyl, which is
found in the linkage region of glycosaminoglycans. It also used simple
beta-galactosides and other glycans with terminal beta-linked Gal
residues. Knockdown of GALTII in HeLa cells inhibited synthesis of both
heparan sulfate and chondroitin sulfate.

GENE STRUCTURE

Bai et al. (2001) determined that B3GALT6 is a single-exon gene.

MAPPING

By genomic sequence analysis, Bai et al. (2001) mapped the B3GALT6 gene
to chromosome 1p36.3. They mapped the mouse B3galt6 gene to a region of
chromosome 4E2 that shares homology of synteny with human chromosome
1p36.3.

MOLECULAR GENETICS

- Spondyloepimetaphyseal Dysplasia with Joint Laxity, Type
1, with or without Fractures

By next-generation sequencing in 7 individuals, including 2 sibs, with
spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1;
271640) from 5 unrelated Japanese families and a Singapore/Japanese
family, Nakajima et al. (2013) identified possible mutations in the
B3GALT6 gene. By direct sequencing of this gene in these 7 patients and
an additional patient with JEMDJL1 from a Vietnamese family, they
identified compound heterozygous missense mutations in all but 1 in whom
a second mutation was not found (615291.0001-615291.0006). One of the
mutations (M1?; 615291.0001) was found in 5 of the 7 families. None of
the mutations were found in 200 ethnically matched controls or in public
databases, including the 1000 Genomes Database. Immunocytochemical
studies of mutant proteins showed subcellular mislocalization of all but
2 (D156N, 615291.0003 and C300S, 615291.0004). Galt-II activities of all
mutant proteins were significantly decreased compared to wildtype,
indicating loss of function. There were no significant differences in
GALT-II activities between wildtype and a common B3GALT6 polymorphism
(dbSNP rs12085009). Biochemical studies using patient lymphoblastoid
cells showed a decrease of heparan sulfate and a paradoxical increase of
chondroitin sulfate and dermatan sulfate on the cell surface.

By homozygosity mapping and candidate gene sequence analysis in 3
unrelated Iranian families segregating SEMDJL1 with fractures, Malfait
et al. (2013) identified homozygous or compound heterozygous mutations
in the B3GALT6 gene (615291.0012-615291.0014), which segregated with the
disorder in each family. Patient fibroblasts exhibited a large decrease
in ability to prime glycosaminoglycan synthesis together with impaired
glycanation of the small chondroitin/dermatan sulfate proteoglycan
decorin, confirming B3GALT6 loss of function. Dermal electron microscopy
showed abnormalities in collagen fibril organization. A strong reduction
in heparan sulfate level was also observed, indicating that B3GALT6
deficiency alters synthesis of both main types of glycosaminoglycans. An
in vitro wound healing assay revealed a significant delay in fibroblasts
from 2 index individuals, pointing to a role for glycosaminoglycan
defect in impaired wound repair in vivo.

- Ehlers-Danlos Syndrome, Progeroid Type, 2

Because some of the patients with SEMDJL1 in whom they had identified
mutations in the B3GALT6 gene had some overlapping features with the
progeroid form of Ehlers-Danlos syndrome (615349), Nakajima et al.
(2013) performed Sanger sequencing of the B3GALT6 gene in 4 EDSP
patients from 3 families who did not have a mutation in the B4GALT7 gene
(604327). All 4 patients were found to be compound heterozygous for a
frameshift and a missense mutation in the B3GALT6 gene
(615291.0007-615291.0011). A missense mutation that was common in 2 EDSP
families (S309T; 615291.0008) was found to have significantly decreased
GalT-II activities compared to wildtype, indicating loss of function.
None of the mutations were found in 200 ethnically matched controls or
in public databases, including the 1000 Genomes Database.

ANKRD65

dbSNP name	rs143038747(G,A); rs1781132(C,T); rs904589(C,G); rs3766165(A,G); rs12089560(A,G)
cytoBand name	1p36.33
EntrezGene GeneID	441869
snpEff Gene Name	RP4-758J18.6
EntrezGene Description	ankyrin repeat domain 65
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.04224

ATAD3A

dbSNP name	rs151027309(A,T); rs140927356(C,A); rs150199746(T,G); rs6669795(A,C); rs9439458(T,C); rs141627726(G,C); rs150520639(T,C); rs113751252(G,T); rs1077906(A,G); rs146756261(G,C); rs9439441(G,A); rs189196817(T,A); rs183883762(C,T); rs61226390(G,A); rs138757840(G,A); rs3813216(A,G); rs3737714(C,T); rs112869160(T,C); rs201275592(G,A); rs10796394(C,T); rs3128345(A,G); rs116279124(C,T); rs6684212(C,T); rs9439462(C,T); rs78493114(G,C); rs11260608(C,A); rs9439443(C,T); rs114845849(G,A); rs182958394(C,T); rs112624192(G,C); rs149348995(G,A); rs144698654(G,A); rs12032637(A,G); rs115990140(G,A); rs6683520(C,T); rs6688404(A,G); rs1987191(T,C); rs6677993(G,A); rs145341309(C,T)
ccdsGene name	CCDS53260.1
cytoBand name	1p36.33
EntrezGene GeneID	55210
EntrezGene Description	ATPase family, AAA domain containing 3A
EntrezGene Type of gene	protein-coding
Annovar Function	ATAD3A:NM_018188:exon16:c.C1865T:p.A622V,ATAD3A:NM_001170536:exon16:c.C1484T:p.A495V,ATAD3A:NM_001170535:exon16:c.C1721T:p.A574V,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.5571
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	D2K8Q1
dbNSFP KGp1 AF	0.003663003663
dbNSFP KGp1 Afr AF	0.0142276422764
dbNSFP KGp1 Amr AF	0.0
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.00131926121372
dbSNP GMAF	0.003673
ESP Afr MAF	0.008398
ESP All MAF	0.002999
ESP Eur/Amr MAF	0.000233
ExAC AF	9.760e-04,4.067e-05

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Isolated cases

GROWTH:
[Height];
Short stature;
[Other];
Growth retardation, pre- and postnatal

HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
High forehead;
Frontal bossing;
Midface hypoplasia;
Small mandible;
Long face;
Hypotonic face;
Smooth philtrum;
[Ears];
Low-set ears;
[Eyes];
Downslanting palpebral fissures;
[Nose];
Prominent nasal bridge;
Thin nose;
Long nose;
Bulbous nasal tip;
[Mouth];
High-arched palate;
Cleft palate;
Small mouth;
[Teeth];
Delayed primary dentition;
Crowded teeth;
Oligodontia;
Peg-shaped teeth

ABDOMEN:
[External features];
Inguinal hernia

SKELETAL:
[Hands];
Camptodactyly;
Arachnodactyly;
[Feet];
Pes equinovarus

SKIN, NAILS, HAIR:
[Skin];
Thin skin;
[Nails];
Dysplastic nails;
[Hair];
Thin, sparse hair

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Poor speech development;
Broad-based gait;
[Behavioral/psychiatric manifestations];
Hyperactivity;
Aggression;
Happy demeanor

LABORATORY ABNORMALITIES:
Some patients carry a deletion of minimum of 8.1 Mb on 2q32-q33

MISCELLANEOUS:
Variable manifestations

MOLECULAR BASIS:
Caused by mutation in the special AT-rich sequence-binding protein
2 gene (SATB2, 608148.0001)

OMIM Title
*612316 ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 3A; ATAD3A

OMIM Description

DESCRIPTION

ATAD3A and ATAD3B (612317) are mitochondrial membrane proteins that
contribute to the stabilization of large mitochondrial DNA
(mtDNA)-protein complexes called nucleoids (He et al., 2007).

CLONING

Using mass spectroscopy to identify cell surface antigens on myeloid
cell lines, followed by RT-PCR of promyelocytic cell line RNA, Geuijen
et al. (2005) cloned ATAD3A. Western blot analysis detected ATAD3A at an
apparent molecular mass of 75 kD in transfected human embryonic kidney
(HEK293T) cells. Flow cytometry revealed ATAD3A on the cell surface of a
promyelocytic cell line, on 77% of AML (601626) samples, on half of
monocytes, and on a subpopulation of dendritic cells, but not on other
lymphocytes. ATAD3A was not expressed on the surface of transfected
HEK293T cells.

By searching for sequences similar to rat Atad3, He et al. (2007)
identified human ATAD3A and ATAD3B. In its C-terminal half, the deduced
587-amino acid ATAD3A protein contains Walker A and B motifs, followed
by ATP-binding sensor-1 and sensor-2 motifs. An alpha helix is located
N-terminal to the Walker A motif, and an arginine finger separates the
sensor motifs. An antibody that did not differentiate between ATAD3A and
ATAD3B detected ATAD3 in a punctate pattern within mitochondria of human
osteosarcoma cells. The pattern frequently coincided with
mtDNA-containing nucleoids, but not all nucleoids contained ATAD3.

Bogenhagen et al. (2008) stated that ATAD3A contains a central
transmembrane domain. Using immunofluorescence and protease
susceptibility studies, they found that ATAD3A was embedded in the inner
membrane of HeLa cell mitochondria, with the C-terminal AAA domain
directed toward the matrix and the N terminus exposed to the cytoplasm.

GENE FUNCTION

He et al. (2007) found that depletion of ATAD3 via small interfering RNA
in human osteosarcoma cells led to increased negative supercoiling of
mtDNA, although mitochondria maintained essentially normal morphology.

Bogenhagen et al. (2008) found that, although both ATAD3A and ATAD3B
were present in native HeLa cell nucleoids, neither ATAD3 protein was
crosslinked with mtDNA in isolated formaldehyde crosslinked HeLa cell
nucleoids, indicating that they are unlikely to bind mtDNA. In addition,
protease susceptibility studies suggested that the putative N-terminal
DNA-binding regions of ATAD3A and ATAD3B reside outside the
mitochondrial inner membrane.

MAPPING

Bogenhagen et al. (2008) stated that the ATAD3 locus is tandemly
duplicated in humans, generating 2 paralogs, ATAD3A and ATAD3B. The
ATAD3 genes are located on chromosome 1p36.33 (Schaffrik et al., 2006).

C1orf233

dbSNP name	rs28737320(C,G)
cytoBand name	1p36.33
EntrezGene GeneID	643988
snpEff Gene Name	RP11-345P4.5
EntrezGene Description	chromosome 1 open reading frame 233
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	utr_3_prime
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.1097

TMEM52

dbSNP name	rs4459050(T,C)
ccdsGene name	CCDS35.1
cytoBand name	1p36.33
EntrezGene GeneID	339456
EntrezGene Description	transmembrane protein 52
EntrezGene Type of gene	protein-coding
Annovar Function	TMEM52:NM_178545:exon5:c.A421G:p.M141V,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.0
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	Q8NDY8
dbNSFP Uniprot ID	TMM52_HUMAN
dbNSFP KGp1 AF	0.14880952381
dbNSFP KGp1 Afr AF	0.367886178862
dbNSFP KGp1 Amr AF	0.0994475138122
dbNSFP KGp1 Asn AF	0.131118881119
dbNSFP KGp1 Eur AF	0.0435356200528
dbSNP GMAF	0.1488
ESP Afr MAF	0.333182
ESP All MAF	0.138628
ESP Eur/Amr MAF	0.038953
ExAC AF	0.116

LOC100129534

dbSNP name	rs1039063(T,G); rs10910053(G,A); rs72642166(C,T); rs76142101(C,T); rs61762095(T,G); rs2279704(C,T); rs2254874(G,C); rs2036082(C,T); rs4648831(C,T); rs2840525(A,G); rs2840526(T,C); rs2643912(G,T); rs2840528(A,G); rs2645082(T,C)
ccdsGene name	CCDS40.1
cytoBand name	1p36.33
EntrezGene GeneID	100129534
snpEff Gene Name	MORN1
EntrezGene Description	small nuclear ribonucleoprotein polypeptide N pseudogene
EntrezGene Type of gene	pseudo
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.4591

LOC115110

dbSNP name	rs2147905(T,C); rs3748825(T,C); rs2985858(C,G)
cytoBand name	1p36.32
EntrezGene GeneID	115110
snpEff Gene Name	TNFRSF14
EntrezGene Description	uncharacterized LOC115110
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	upstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.4096

LOC100133445

dbSNP name	rs2227312(C,A); rs2227313(T,C); rs2234152(C,T)
cytoBand name	1p36.32
EntrezGene GeneID	100133445
snpEff Gene Name	TNFRSF14
EntrezGene Description	uncharacterized LOC100133445
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.466
ExAC AF	0.398

ACTRT2

dbSNP name	rs4576609(C,T); rs3795262(T,G)
ccdsGene name	CCDS45.1
cytoBand name	1p36.32
EntrezGene GeneID	140625
EntrezGene Description	actin-related protein T2
EntrezGene Type of gene	protein-coding
Annovar Function	ACTRT2:NM_080431:exon1:c.C15T:p.H5H,
Annovar Mutation type	synonymous SNV
Annovar Region type	exonic
snpEff Effect	synonymous_coding
snpEff Functional Class	silent
snpEff Gene Biotype	protein_coding
snpEff Impact	low
dbSNP GMAF	0.2461
ESP Afr MAF	0.141625
ESP All MAF	0.166154
ESP Eur/Amr MAF	0.178721
ExAC AF	0.191

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Corneal opacities, bilateral superior;
Cornea guttata;
Corectopia;
Normal lens;
Normal retina;
Normal vitreous

MISCELLANEOUS:
One report of mother and son (last curated August 2012)

OMIM Title
*608535 ACTIN-RELATED PROTEIN T2; ACTRT2
;;ARPT2;;
ACTIN-RELATED PROTEIN M2; ARPM2

OMIM Description

CLONING

By searching an EST database for actin-related proteins, Harata et al.
(2001) identified ARPM2. The deduced 377-amino acid protein contains an
actin-like ATP/ADP-binding pocket and 2 nuclear export signals. However,
residues likely to be involved in actin-actin and actin-myosin (see
160730) contacts are not well conserved in ARPM2. ARPM2 shares 48% amino
acid identity with beta-actin (102630) and 46% identity with ARPM1
(608534). RT-PCR detected ARPM2 expression in all tissues tested; the
level of expression was lower than that of beta-actin.

Heid et al. (2002) purified bovine Arpm2, which they designated Arpt2,
from the calyx fraction of epididymal sperm heads. Using peptide
sequences to search genomic and EST databases, they identified human
ARPM2. The ARPM2 protein shares 75.5% amino acid identity with ARPT1
(300487). ARPT1 and ARPM2 contain several cysteine residues not found in
beta-actin or other ARPs. Bovine Arpm2 showed an apparent molecular mass
of about 40 kD.

MAPPING

Harata et al. (2001) mapped the ARPM1 gene in silico to chromosome
1p36.32.

NPHP4

dbSNP name	rs11121648(T,G); rs1287635(T,C); rs1287634(G,A); rs61002800(G,C); rs489933(C,T); rs12078643(C,T); rs555164(T,C); rs12122135(A,G); rs1287630(G,A); rs12405167(G,A); rs1287629(A,G); rs1287626(G,A); rs11804710(G,C); rs522985(A,G); rs499509(A,G); rs472651(C,T); rs115555125(C,T); rs905469(A,G); rs905468(C,T); rs114139049(C,T); rs868162(C,T); rs112284157(C,T); rs868163(A,G); rs905467(T,C); rs1287638(C,T); rs1287637(A,T); rs75450202(G,A); rs1622955(T,C); rs3747992(G,A); rs114545322(C,T); rs3747989(C,T); rs3747988(A,C); rs17432121(C,A); rs114573460(C,T); rs11121915(T,G); rs145926393(G,A); rs9661673(C,T); rs1287625(A,G); rs115187086(G,A); rs115534043(C,T); rs4845828(T,C); rs11121956(C,T); rs116463761(G,A); rs79321451(C,A); rs72630607(G,A); rs115932716(G,A); rs34251435(A,T); rs12079601(A,G); rs4908559(A,G); rs116462647(T,C); rs10779788(G,A); rs114871545(T,C); rs12735231(G,A); rs10746504(T,C); rs2282281(G,A); rs487654(C,T); rs494611(A,G); rs12081133(T,C); rs7550218(C,T); rs138403111(G,A); rs115994790(G,C); rs11122104(C,T); rs11122107(G,A); rs6689443(C,T); rs72856200(A,C); rs17028870(A,G); rs12134240(T,C); rs7519953(A,G); rs10864631(T,C); rs11586334(T,C); rs11577514(C,G); rs56270325(A,T); rs76984673(C,T); rs114545811(C,T); rs2312464(A,G); rs116336807(G,C); rs72857405(T,C); rs10864632(C,T); rs182101894(A,T); rs11122117(C,G); rs2134551(G,A); rs146881978(T,C); rs4908936(A,C); rs12090534(G,A); rs12084678(T,C); rs12062053(C,T); rs57446086(G,A); rs11122125(A,G); rs571655(C,T); rs12093500(G,C); rs3747987(T,C); rs11122130(A,G); rs143436710(C,T); rs115400440(T,G); rs17028879(C,T); rs6692955(G,A); rs72857418(A,G); rs115756609(G,A); rs12069778(C,T); rs12057165(A,G); rs12072386(C,G); rs12060900(G,A); rs12057260(A,C); rs6694744(A,G); rs192130523(G,A); rs138647234(C,T); rs183551539(G,T); rs142066786(G,A); rs150680594(C,T); rs515628(C,T); rs11120772(G,A); rs145095236(C,T); rs72857438(C,A); rs143158375(G,A); rs140412661(G,A); rs1889971(A,G); rs12086103(G,A); rs147540617(T,C); rs150957294(G,A); rs11587302(G,A); rs61762117(T,C); rs140458228(C,G); rs114398063(C,T); rs7549818(A,G); rs78825568(G,A); rs55676949(G,C); rs35291001(T,C); rs962662(G,A); rs142098216(G,A); rs139258970(G,C); rs72857448(G,A); rs72857450(T,C); rs11120781(T,C); rs7549324(G,A); rs11120782(A,G); rs10864245(G,A); rs7535806(G,A); rs7549369(A,C); rs144468751(A,G); rs12745546(C,A); rs142205176(G,A); rs1011994(C,T); rs149784548(T,C); rs2174124(T,C); rs35760537(G,A); rs143371979(G,A); rs148376780(T,A); rs150729272(C,T); rs139897549(G,T); rs7519679(T,C); rs7548619(G,A); rs7520105(T,C); rs11590397(G,A); rs115875752(G,A); rs11590436(G,T); rs149015647(A,T); rs12742075(A,G); rs11120805(A,G); rs11120806(C,T); rs144633876(C,A); rs12353987(C,T); rs4908583(C,T); rs10864262(T,C); rs149529921(G,A); rs9727119(A,C); rs10864264(C,T); rs145863282(T,C); rs140798376(A,G); rs11576617(C,T); rs72857457(A,T); rs115413424(G,C); rs114297856(C,A); rs869107(G,C); rs12098207(G,A); rs521736(A,G); rs144741296(G,T); rs12058794(G,A); rs34713106(T,C); rs35078529(C,T); rs114271135(G,A); rs35685456(G,A); rs116227781(G,A); rs12060459(G,A); rs12065728(C,T); rs1466923(A,G); rs72857466(T,C); rs11120832(T,C); rs144631422(G,A); rs141419442(A,G); rs114484312(G,A); rs2062784(T,C); rs12734220(A,G); rs12070803(A,G); rs2152922(G,C); rs138797443(T,C); rs150365587(C,T); rs12033563(T,C); rs143675266(T,C); rs11804463(A,G); rs1566724(G,A); rs34921218(A,G); rs140899058(G,A); rs150173097(C,T); rs145031110(T,C); rs144803499(C,G); rs6676029(G,A); rs72857479(G,A); rs551207(C,T); rs10779677(G,A); rs12032639(A,G); rs11120871(C,T); rs115534498(T,C); rs10864284(G,C); rs139399261(G,A); rs693005(A,G); rs11120875(G,A); rs6702707(C,T); rs146754523(C,G); rs12076999(C,T); rs6659420(A,G); rs114263507(A,G); rs6662680(T,C); rs72857494(G,A); rs56127510(A,G); rs6691541(C,G); rs113924109(G,A); rs6699722(T,C); rs115748491(G,A); rs7555293(T,C); rs35206665(G,A); rs34188627(G,A); rs35716311(T,A); rs11584087(T,C); rs143356904(G,A); rs35269427(G,A); rs34444818(G,C); rs6660956(T,C); rs17028951(G,C); rs12074103(G,A); rs58392806(T,C); rs12076826(G,A); rs10864292(T,C); rs2011197(C,T); rs111987560(T,A); rs72859112(T,C); rs72859114(T,G); rs72859116(C,G); rs72859118(C,G); rs72859122(G,A); rs115772366(T,C); rs12083678(C,T); rs61762129(T,C); rs113011789(A,G); rs11587241(A,C); rs10779681(T,C); rs10779682(C,A); rs11120898(C,T); rs7522246(T,C); rs7515065(C,T); rs7515070(C,T); rs35357995(T,C); rs61762132(C,T); rs6666684(C,T); rs71629759(G,A); rs2050653(G,A); rs875574(C,A); rs875573(A,G); rs12084942(C,T); rs871780(G,A); rs4908628(A,G); rs12137358(C,G); rs140233544(T,C); rs553959(T,C); rs143087336(T,C); rs2275231(T,C); rs12729290(A,T); rs12745395(G,A); rs34768831(G,T); rs2047811(T,G); rs11588889(C,A); rs6694797(A,G); rs12091974(C,G); rs2062785(C,T); rs186055712(T,G); rs116537682(T,C); rs11585166(G,C); rs146412778(T,C); rs11586662(C,A); rs12409002(T,C); rs4908458(C,T); rs4068401(T,C); rs4068400(G,A); rs4068399(G,A); rs147223718(G,A); rs115036756(T,A); rs116777435(C,A); rs4908638(C,T); rs12084871(G,A); rs76260062(A,T); rs11586352(G,A); rs57270677(G,C); rs485942(A,T); rs34794580(C,T); rs2312050(C,A); rs72859153(G,C); rs151164872(A,C); rs882128(T,C); rs115886975(C,T); rs11120933(G,A); rs1287543(C,T); rs11120934(G,A); rs4908639(G,C); rs114368032(C,G); rs4908641(G,T); rs72859167(T,C); rs10779685(T,C); rs496739(A,C); rs34501422(G,A); rs11120951(T,C); rs116382749(T,C); rs806103(G,A); rs72630649(C,T); rs806104(G,A); rs146042177(C,T); rs7552237(T,C); rs812051(G,A); rs116717649(C,A); rs6577448(G,A); rs1295111(C,G); rs145551188(T,G); rs806105(A,G); rs138294503(A,C); rs709207(C,T); rs806106(C,T); rs138589503(G,C); rs11577700(C,T); rs806107(A,G); rs140320318(G,C); rs806108(C,G)
ccdsGene name	CCDS44052.1
cytoBand name	1p36.31
EntrezGene GeneID	261734
EntrezGene Description	nephronophthisis 4
EntrezGene Type of gene	protein-coding
Annovar Function	NPHP4:NM_001291593:exon12:c.G313A:p.E105K,NPHP4:NM_015102:exon15:c.G1852A:p.E618K,NPHP4:NM_001291594:exon11:c.G316A:p.E106K,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.6339
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	retained_intron
snpEff Impact	moderate
dbNSFP Uniprot Acc	O75161
dbNSFP Uniprot ID	NPHP4_HUMAN
dbNSFP KGp1 AF	0.00824175824176
dbNSFP KGp1 Afr AF	0.0020325203252
dbNSFP KGp1 Amr AF	0.00828729281768
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0184696569921
dbSNP GMAF	0.008264
ESP Afr MAF	0.003544
ESP All MAF	0.011218
ESP Eur/Amr MAF	0.014847
ExAC AF	0.01

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Head];
Acquired microcephaly (in severe cases);
[Eyes];
Visual impairment, cortical (in severe cases)

NEUROLOGIC:
[Central nervous system];
Generalized clonic or tonic-clonic seizures;
Unilateral clonic seizures;
Absence seizures;
Complex partial seizures;
Myoclonic seizures;
Delayed psychomotor development;
Psychomotor delay after second year;
Mental deterioration;
Ataxia;
Status epilepticus;
EEG may be normal at first;
EEG later shows generalized spike or polyspike waves and focal spikes;
EEG may show migrating focal or multifocal origin (in severe cases);
Cerebral atrophy (in severe cases)

MISCELLANEOUS:
Marked phenotypic variability;
Most mutations occur de novo;
Onset in first year of life;
Psychomotor delay may already be apparent at onset of seizures;
May be induced by fever or hot bath;
Often refractory to medical therapy;
May be extreme phenotype of generalized epilepsy with febrile seizures
plus (GEFS+, 604233)

MOLECULAR BASIS:
Caused by mutation in the alpha subunit of the voltage-gated sodium
channel type I gene (SCN1A, 182389.0007);
Caused by mutation in the alpha subunit of the voltage-gated sodium
channel type IX gene (SCN9A, 603415.0019);
Caused by mutation in the gamma-aminobutyric acid (GABA) A receptor,
gamma-2 gene (GABRG2, 137164.0003)

OMIM Title
*607215 NEPHROCYSTIN 4; NPHP4
;;KIAA0673;;
NEPHRORETININ

OMIM Description

CLONING

Using markers covering the nephronophthisis-4 (NPHP4; 606966) locus on
1p36, Mollet et al. (2002) carried out haplotype analysis of families
affected with nephronophthisis that were not linked to previously
identified nephronophthisis loci. They narrowed the NPHP4 critical
interval to a 1-cM region containing 6 genes, the sequences of which
were available in public databases. They detected 5 mutations in the
coding region of the KIAA0673 gene, which had been shown by Ishikawa et
al. (1998) to be expressed in the kidney and was predicted to encode a
protein containing an SH3-interacting motif. Northern blot analysis
using a partial NPHP4 cDNA detected weak expression of 2 major
transcripts of approximately 4.5 and 7.5 kb in kidney, skeletal muscle,
heart, and liver, and to a lesser extent in brain and lung. Mollet et
al. (2002) obtained a full-length NPHP4 cDNA by 5-prime and 3-prime
RACE-PCR and RT-PCR. They stated that NPHP4 gene encodes a 1,250-amino
acid protein that shares 86% identity with the mouse ortholog. In an
erratum, they indicated that an error in sequence analysis had led to
the masking of a methionine codon located 176 amino acids upstream of
the previously reported initiation codon. Correction of this error
indicated that NPHP4 contains 1,426 amino acids.

By use of high-resolution haplotype analysis and by demonstration of 9
likely loss-of-function mutations in 6 affected families with NPHP4,
Otto et al. (2002) also identified the NPHP4 gene. They found that the
deduced 1,426-amino acid protein, which they called nephroretinin, is
highly conserved in evolution, with a homolog in C. elegans. Northern
blot analysis revealed broad expression of a 5-kb transcript, with
strong expression in skeletal muscle; dot blot analysis detected strong
expression in skeletal muscle and testis.

By immunostaining mouse retina, Roepman et al. (2005) determined that
Nphp1 was expressed in branching processes emanating from inner nuclear
neurons, in the postsynaptic layer of the outer plexiform layer, and in
cell bodies of photoreceptors. It also localized diffusely in the inner
segment compartment of photoreceptors.

GENE STRUCTURE

Mollet et al. (2002) and Otto et al. (2002) determined that the NPHP4
gene contains 30 exons.

MAPPING

Mollet et al. (2002) and Otto et al. (2002) independently cloned the
NPHP4 gene from the nephronophthisis-4 critical interval on 1p36.

GENE FUNCTION

Mollet et al. (2002) demonstrated the interaction of NPHP4 with NPHP1
(607100), suggesting that these 2 proteins participate in a common
signaling pathway.

Mollet et al. (2005) demonstrated that NPHP4 localized to the primary
cilia in polarized epithelial tubular cells, particularly at the basal
bodies, and associated with alpha-tubulin (see 602529), suggesting a
common role for the nephrocystin proteins in ciliary function. However,
NPHP4 was also detected at the centrosomes of dividing cells and close
to the cortical actin cytoskeleton in polarized cells. The proteins
p130Cas (BCAR1; 602941) and PTK2B (601212) were also detected in the
NPHP4-containing complex, confirming the role of the nephrocystin
proteins in cell-cell and cell-matrix adhesion signaling events. Mollet
et al. (2005) suggested that NPHP1 and NPHP4 belong to a multifunctional
complex localized in actin- and microtubule-based structures involved in
cell-cell and cell-matrix adhesion signaling, as well as in cell
division.

By yeast 2-hybrid analysis, Roepman et al. (2005) determined that NPHP4
interacted with C2 domain-containing RPGRIP1 (605446) isoforms. Analysis
of the interaction in the presence of Ca(2+) chelators indicated that
the binding was Ca(2+) independent. NPHP1 colocalized with C2-containing
RPGRIP1 isoforms in bovine and mouse retina. Mutations in NPHP4
associated with Senior-Loken syndrome-4 (606996) and mutations in RPGRP1
associated with Leber congenital amaurosis-6 (605446) disrupted the
interaction between the 2 proteins.

Delous et al. (2009) showed that nephrocystin mRNA expression was
dramatically increased during cell polarization, and shRNA-mediated
knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed
tight junction (TJ) formation, abnormal cilia formation, and
disorganized multilumen structures when grown in a 3-dimensional
collagen matrix. Some of these phenotypes were similar to those reported
for cells depleted of the TJ proteins PALS1 (MPP5; 606958) or PAR3
(PARD3; 606745). A physical interaction between these nephrocystins and
PALS1 as well as their partners PATJ (INADL; 603199) and PAR6 (PARD6A;
607484) was demonstrated, and the proteins partially colocalized in
human renal tubules. The authors concluded that the nephrocystins play
an essential role in epithelial cell organization, suggesting a
mechanism by which the histopathologic features of nephronophthisis
might develop.

Williams et al. (2011) showed that the conserved proteins Mks1 (609883),
Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67 (609884), Rpgrip1l (610937),
Cc2d2a (612013), Nphp1, and Nphp4 functioned at an early stage of
ciliogenesis in C. elegans. These 8 proteins localized to the ciliary
transition zone and established attachments between the basal body and
transition zone membrane. They also provided a docking site that
restricted vesicle fusion to vesicles containing ciliary proteins.

MOLECULAR GENETICS

- Nephronophthisis 4

In patients with juvenile nephronophthisis mapping to 1p36 (NPHP4;
606966), Mollet et al. (2002) found 5 mutations in the NPHP4 gene: 3
nonsense, 1 frameshift, and 1 missense (607215.0001-607215.0005). The
nonsense and frameshift mutations resulted in putative truncated
proteins, and the missense mutation affected a residue within a highly
conserved motif. Because of an error in the original sequencing of the
NPHP4 gene, Mollet et al. (2002) published a table with the revised
designations of the mutations.

Otto et al. (2002) demonstrated mutations in the NPHP4 gene in patients
with juvenile nephronophthisis.

- Senior-Loken Syndrome 4

Otto et al. (2002) identified 2 loss-of-function mutations in the NPHP4
gene (607215.0006-607215.0007) in patients with Senior-Loken syndrome-4
(SLSN4; 606996), demonstrating that NPHP4 and SLSN4 are allelic.

HES2

dbSNP name	rs1054274(T,G); rs1054273(C,A); rs11364(C,T); rs141712069(C,T); rs4908889(A,G); rs113269467(T,C); rs78326109(C,G); rs61780700(A,G); rs142559010(T,C); rs190274993(C,T)
cytoBand name	1p36.31
EntrezGene GeneID	54626
EntrezGene Description	hes family bHLH transcription factor 2
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.2746

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Loss of consciousness due to hypoglycemia;
Seizures, hypoglycemic

ENDOCRINE FEATURES:
Hyperinsulinemic hypoglycemia

LABORATORY ABNORMALITIES:
Hypoglycemia, postprandial;
Hyperinsulinemia, fasting;
Elevated serum insulin-to-C-peptide ratio

MISCELLANEOUS:
Genetic heterogeneity (see HHF1 256450)

MOLECULAR BASIS:
Caused by mutation in the insulin receptor gene (INSR, 147670.0037)

OMIM Title
*609970 HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 2; HES2

OMIM Description

CLONING

By searching databases using mouse Hes2 as query, Katoh and Katoh (2004)
identified human HES2. The deduced 173-amino acid protein contains an
N-terminal basic helix-loop-helix domain, followed by an orange domain,
a proline-rich domain, and a C-terminal WRPW motif. HES2 ESTs were found
in a placenta cDNA library and in several cancer cDNA libraries.

GENE STRUCTURE

Katoh and Katoh (2004) determined that the HES2 gene contains 4 exons.

MAPPING

By genomic sequence analysis, Katoh and Katoh (2004) mapped the HES2 and
HES3 (609971) genes to chromosome 1p36.31.

ENO1-AS1

dbSNP name	rs1325920(G,A)
cytoBand name	1p36.23
EntrezGene GeneID	100505975
snpEff Gene Name	ENO1
EntrezGene Description	ENO1 antisense RNA 1
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	upstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.191

H6PD

dbSNP name	rs11121349(G,C); rs56119172(C,G); rs55858522(G,A); rs12126056(G,A); rs4908830(A,G); rs181808395(C,T); rs6685399(C,T); rs2268176(T,G); rs1294011(G,T); rs2268175(T,C); rs2268174(C,A); rs2268173(T,C); rs2268172(C,A); rs9435148(G,C); rs12405956(G,A); rs2268171(C,T); rs56108736(G,C); rs6658895(G,A); rs186416946(T,C); rs2239561(A,G); rs2239560(G,A); rs76637581(G,A); rs2310925(T,C); rs7524046(G,A); rs11121350(T,C); rs12032814(T,A); rs11804534(T,C); rs57823928(G,C); rs11804519(A,G); rs9434732(G,T); rs9435151(C,T); rs1294010(T,C); rs732950(G,T); rs763180(G,A); rs9435155(T,C); rs9434736(G,C); rs12083129(G,A); rs7526864(A,G); rs201697732(T,C); rs60659154(G,A); rs9435156(A,G); rs61785090(G,A); rs2268170(C,T); rs6662509(C,T); rs80265342(A,G); rs3753165(T,C); rs3753164(A,G); rs9435158(C,T); rs2268169(G,A); rs185590012(G,C); rs150901527(C,T); rs111798710(A,G); rs114466775(T,C); rs113705107(T,C); rs731183(G,C); rs6688832(G,A); rs17368528(C,T); rs9434742(T,C); rs9434743(A,G); rs17368633(G,T); rs9435159(C,T); rs1294014(C,T); rs72641816(A,T); rs72641817(C,T); rs45491397(G,T); rs1294015(T,G); rs11121354(T,G); rs12314(A,C); rs57355294(G,A); rs9434747(T,C); rs3207316(C,T); rs2071931(C,T); rs61740358(C,T); rs11121356(C,T); rs12144045(G,C); rs1138467(T,C); rs9435163(G,T); rs9435164(A,T)
ccdsGene name	CCDS101.1
cytoBand name	1p36.22
EntrezGene GeneID	9563
EntrezGene Description	hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase)
EntrezGene Type of gene	protein-coding
Annovar Function	H6PD:NM_001282587:exon4:c.C934T:p.R312W,H6PD:NM_004285:exon4:c.C901T:p.R301W,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.9852
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	O95479
dbNSFP Uniprot ID	G6PE_HUMAN
dbNSFP KGp1 AF	0.000457875457875
dbNSFP KGp1 Afr AF	0.0
dbNSFP KGp1 Amr AF	0.0
dbNSFP KGp1 Asn AF	0.00174825174825
dbNSFP KGp1 Eur AF	0.0
dbSNP GMAF	4.591E-4
ESP Afr MAF	0.0
ESP All MAF	0.000154
ESP Eur/Amr MAF	0.000233
ExAC AF	2.846e-04,1.627e-05

*OMIM Information*

OMIM Clinical Significance

Lab:
Renal glycosuria;
Hyperglycinuria

Inheritance:
Autosomal dominant

OMIM Title
*138090 HEXOSE-6-PHOSPHATE DEHYDROGENASE; H6PD
;;GLUCOSE DEHYDROGENASE; GDH;;
GDH/6PGL ENDOPLASMIC BIFUNCTIONAL PROTEIN;;
HEXOSE-6-PHOSPHATE DEHYDROGENASE PRECURSOR;;
GLUCOSE-6-PHOSPHATE DEHYDROGENASE, SALIVARY;;
G6PD, H FORM; G6PDH;;
GLUCOSE 1-DEHYDROGENASE

OMIM Description

DESCRIPTION

Glucose dehydrogenase (GDH), or hexose-6-phosphate dehydrogenase (H6PD;
EC 1.1.1.47), is a microsomal enzyme with a dimeric structure that
oxidizes glucose-6-phosphate, glucose, galactose-6-phosphate, and
2-deoxyglucose-6-phosphate using NAD or NADP as coenzymes (summary by
Krczal et al., 1993).

CLONING

Mason et al. (1999) isolated and sequenced a cDNA encoding human H6PD.
The deduced protein contains 791 amino acids and shares extensive
homology with cytosolic G6PD (305900). H6PD is present in most tissues,
predominantly in liver, but is not present in red cells (Beutler and
Morrison, 1967; Mason et al., 1999).

GENE STRUCTURE

Mason et al. (1999) determined that the H6PD gene spans 37 kb and
contains 5 exons, the fifth of which codes for more than half of the
89-kD protein.

MAPPING

Hameister et al. (1978) showed by somatic cell hybridization that GDH is
on chromosome 1. The locus is closely linked (theta less than 0.05) to
PGD (172200). King (1982) concluded that GDH is near the end of 1p. The
PGD:Rh distance is about 17 cM in the male and 27 cM in the female;
thus, GDH may be about 12 cM distal to PGD in the male and 19 cM distal
in the female. Carritt et al. (1982) presented evidence that GDH and
ENO1 (172430) are distal to PGD and that all 3 loci are distal to
1p36.13. They presented an updated map of 1p, revising that provided by
HGM6, the Oslo workshop.

By sequence similarity to a human genomic sequence that had been mapped
to chromosome 1p36, Mason et al. (1999) mapped the human H6PD gene to
that region.

GENE FUNCTION

H6PD is able to catalyze the first 2 reactions of an endolumenal pentose
phosphate pathway, thereby generating reduced nicotinamide adenine
dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is
distinct from the cytosolic enzyme G6PD (305900), using a separate pool
of NAD(P)+ and capable of oxidizing several phosphorylated hexoses
(summary by Hewitt et al., 2005).

MOLECULAR GENETICS

- Cortisone Reductase Deficiency 1

In cortisone reductase deficiency (604931), activation of cortisone to
cortisol does not occur, suggesting a defect in 11-beta-hydroxysteroid
dehydrogenase type 1 (HSD11B1; 600713), a primary regulator of
tissue-specific glucocorticoid bioavailability. In vivo,
11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1) catalyzes the
reduction of cortisone to cortisol, whereas purified enzyme acts as a
dehydrogenase, converting cortisol to cortisone. Oxoreductase activity
can be regained via a NADPH-regeneration system involving the cytosolic
enzyme glucose-6-phosphate dehydrogenase (G6PD; 305900); however,
because the catalytic domain of 11-beta-HSD1 faces into the lumen of the
endoplasmic reticulum (ER), Draper et al. (2003) hypothesized that the
endolumenal hexose-6-phosphate dehydrogenase (H6PD) regenerates NADPH in
the ER, thereby influencing directionality of 11-beta-HSD1 activity. In
3 individuals with cortisone reductase deficiency, Draper et al. (2003)
identified intronic mutations in the HSD11B1 gene (see 600713.0001) in
combination with mutations in H6PD (138090.0001, 138090.0002) and
proposed a triallelic digenic model of inheritance.

Noting that large-scale population-based studies from 3 centers (Draper
et al., 2006; Smit et al., 2007; White, 2005) had shown that the
variants found by Draper et al. (2003) were polymorphisms rather than
disease-causing mutations, Lavery et al. (2008) restudied 4 patients
with cortisone reductase deficiency, including the 3 patients studied by
Draper et al. (2003). Lavery et al. (2008) found no mutations or
sequence variants in the HSD11B1 gene. Sequencing of the H6PD gene
revealed 4 novel and 1 previously reported mutation in homozygous or
compound heterozygous state (138090.0003-138090.0006 and 138090.0001,
respectively) in all 4 patients. Expression and activity assays
demonstrated loss of function for all 5 mutations, which were not found
in 120 control chromosomes. Lavery et al. (2008) concluded that
cortisone reductase deficiency can be explained solely by inactivation
of the H6PD gene and stated that in the earlier study by Draper et al.
(2003), these mutations in H6PD were either missed or presumed to be
silent and thus of no relevance.

- Polymorphism

By the zymogram technique, Tan and Ashton (1976) found 3 phenotypes of
G6PD of the H type in human saliva. Family and population studies
suggested that these phenotypes are the products of an autosomal locus
with 2 alleles, Sgd-1 and Sgd-2. In addition to oxidizing other
hexose-6-phosphates, H6PD uses NAD as well as NADP as a coenzyme. It is
present in the microsomes. The existence of a separate G6PD isozyme in
fetal brain was suggested by Toncheva et al. (1982), who thought it was
probably determined by an autosomal gene.

King and Cook (1981) found polymorphism by isoelectric focusing. The
frequency of 3 alleles was found to be 0.723, 0.194, and 0.083. Krczal
et al. (1993) calculated the frequencies of the 3 alleles in
southwestern Germany to be 0.70, 0.18, and 0.12. Data on gene
frequencies of allelic variants were tabulated by Roychoudhury and Nei
(1988).

- Multiple Sclerosis 4

For discussion of a possible association between variation in the H6PD
gene and multiple sclerosis, see MS4 (612596).

ANIMAL MODEL

H6pd-null mice are relatively insensitive to glucocorticoids, exhibiting
fasting hypoglycemia, increased insulin sensitivity despite elevated
circulating corticosterone, and increased basal and insulin-stimulated
glucose uptake in muscle normally enriched in type II (fast) fibers,
which have increased glycogen content. Lavery et al. (2008) found
H6pd-null mice developed severe skeletal myopathy characterized by
switching of type II to type I (slow) fibers. Affected muscles had
normal sarcomeric structure but contained large intrafibrillar
membranous vacuoles, abnormal sarcoplasmic reticulum (SR) structure, and
dysregulated expression of SR proteins involved in calcium metabolism.
There was also overexpression of genes involved in the unfolded protein
response pathway. Lavery et al. (2008) concluded that the absence of
H6PD induces myopathy by altering the SR redox state, thereby impairing
protein folding and activating the unfolded protein response pathway.

MASP2

dbSNP name	rs1033638(A,G); rs138934492(C,T); rs72550845(A,G); rs1782455(G,A); rs1782454(T,C); rs148441597(C,G); rs112338214(T,G); rs1782457(T,A); rs12711521(C,A); rs17409276(G,A); rs114957056(C,T); rs7555145(T,C); rs7555662(A,G); rs7544377(C,G); rs7556039(A,G); rs12755574(G,A); rs11583653(G,A); rs12072993(A,G); rs181112690(A,C); rs11121684(G,A); rs6695096(C,T); rs75943109(G,A); rs11121685(A,T); rs112457053(G,A); rs111984753(G,A); rs113578695(C,T); rs57360396(G,A); rs142692059(C,T); rs12142107(C,T); rs12131963(A,G); rs12136468(G,A); rs6660417(T,A); rs72870056(G,A); rs61535446(A,G); rs72870059(G,A); rs58243167(C,G); rs61773665(G,A); rs61773666(G,A); rs12136082(A,G); rs7536030(G,A); rs7536396(G,A); rs910663(G,A); rs3765900(C,T); rs3765901(G,A); rs3819991(G,A); rs9430347(T,C); rs2273345(C,T); rs2273344(C,T); rs111646202(G,A); rs10779750(T,C); rs201551849(A,C); rs66761147(C,T); rs140239262(G,A); rs367877632(C,T)
ccdsGene name	CCDS123.1
cytoBand name	1p36.22
EntrezGene GeneID	10747
EntrezGene Description	mannan-binding lectin serine peptidase 2
EntrezGene Type of gene	protein-coding
Annovar Function	MASP2:NM_006610:exon11:c.G1903A:p.G635R,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.9544
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	O00187
dbNSFP Uniprot ID	MASP2_HUMAN
dbNSFP KGp1 AF	0.00137362637363
dbNSFP KGp1 Afr AF	0.00609756097561
dbNSFP KGp1 Amr AF	0.0
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0
dbSNP GMAF	0.001377
ExAC AF	6.507e-05

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Alzheimer disease;
Seizures;
Cerebral cortex with spongiform changes;
Neurofibrillary tangles;
Beta-amyloid-positive senile plaques;
Prion protein-positive senile plaques

MISCELLANEOUS:
Age of onset 43-64 years

OMIM Title
*605102 MANNAN-BINDING LECTIN SERINE PROTEASE 2; MASP2
MAP19, INCLUDED

OMIM Description

DESCRIPTION

The complement system is essential for the operation of the innate and
adaptive immune defense. In addition to the classic pathway initiated by
antigen-antibody complexes and the alternative pathway initiated by
structures on microbial surfaces, there is an antibody-independent
pathway that is initiated by binding of the mannan-binding lectin (MBL;
154545), which is structurally related to C1q (see 120550), to
carbohydrates. MBL, the plasma levels of which are genetically
determined, activates the complement pathway through mannan-binding
lectin serine proteases (MASPs), such as MASP2 (summary by Thiel et al.,
1997).

CLONING

Using affinity chromatography to purify carbohydrate-binding plasma
proteins, followed by microsequence analysis and by RT-PCR on a liver
cDNA library, Thiel et al. (1997) identified a cDNA encoding MASP2.
MASP2 was expressed as a 52-kD protein under reducing conditions. The
predicted 686-amino acid MASP2 protein shares 46 to 52% amino acid
similarity (taking into account residues of a similar nature as well as
identical residues) with C1r (613785), C1s (120580), and MASP1 (600521);
these proteins also share the same domain organization. MASP2 contains a
15-amino acid signal peptide, the 3 amino acids essential for the active
center of a serine protease, and calcium-binding residues in the
epidermal growth factor (EGF; 131530)-like domain. Unlike MASP1, MASP2
has no sites for N-linked glycosylation. Overall, MASP1 is most
homologous to C1r and MASP2 is most homologous to C1s, supporting the
notion that the MBL pathway may antedate the development of the specific
immune system of vertebrates.

By screening a liver cDNA library, Stover et al. (1999) identified a
cDNA encoding a shorter variant of MASP2, which they termed MAP19
(MBL-associated plasma protein of 19 kD). The deduced 185-amino acid
MAP19 protein retains the signal peptide, the N-terminal CUB (see CUBN,
602997) domain, and the EGF-like domain of full-length MASP2, but it has
a unique C-terminal sequence (EQSL) and lacks the serine protease
catalytic domain. Northern blot analysis revealed higher expression of
the 1.0-kb MAP19 transcript than of the 2.6-kb transcript encoding the
serine protease domain of MASP2. Immunoblot analysis indicated that
uncleaved MASP2 is expressed as a 76-kD protein, while the A chain has a
molecular mass of 52 kD and the B chain has a mass of 31 kD. Stover et
al. (1999) proposed that MAP19 has a role in modulating the activation
of complement via the MBL pathway.

By biochemical purification of a 22-kD protein associated with MASP1
preparations and peptide sequence analysis, Takahashi et al. (1999)
cloned the short variant of MASP2, which they termed sMAP (small
MBL-associated protein). Northern blot and RT-PCR analyses showed that
MASP2 is expressed in the liver and that the short variant is the major
transcript.

GENE STRUCTURE

By Southern blot analysis, Stover et al. (1999) showed that the MASP2
gene spans less than 22 kb and contains 4 exons. Only the first 2 exons
of MASP2 are used for the MAP19 variant, while full-length MASP2 skips
exon 2. Takahashi et al. (1999) confirmed that MAP19 (sMAP) uses only
exons 1 and 2.

MAPPING

By FISH, Stover et al. (1999) mapped the MASP2 gene to chromosome
1p36.3-p36.2. They confirmed this localization by radiation hybrid
analysis.

GENE FUNCTION

Functional analysis by Thiel et al. (1997) showed that MASP2 activated
C4 (see 120810), a requirement for the generation of a C3
(120700)-converting complex.

MOLECULAR GENETICS

In a patient with MASP2 deficiency (613791), Stengaard-Pedersen et al.
(2003) identified homozygosity for a mutation in exon 3 of the MASP2
gene, resulting in an asp105-to-gly (D105G; 605102.0001) substitution in
the CUB1 domain.

MIR4632

dbSNP name	rs653667(T,G)
ccdsGene name	CCDS145.1
cytoBand name	1p36.22
EntrezGene GeneID	100616438
snpEff Gene Name	TNFRSF1B
EntrezGene Description	microRNA 4632
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.3136
ESP Afr MAF	0.248071
ESP All MAF	0.326849
ESP Eur/Amr MAF	0.367209
ExAC AF	0.337,3.177e-04,1.629e-05

MIR6730

dbSNP name	rs2275874(C,T)
ccdsGene name	CCDS146.1
cytoBand name	1p36.22
EntrezGene GeneID	9249
EntrezGene Symbol	DHRS3
snpEff Gene Name	DHRS3
EntrezGene Description	dehydrogenase/reductase (SDR family) member 3
EntrezGene Type of gene	protein-coding
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.3797
ESP Afr MAF	0.174762
ESP All MAF	0.418192
ESP Eur/Amr MAF	0.457093
ExAC AF	0.491

PRAMEF12

dbSNP name	rs1812242(T,C); rs372043644(G,A); rs848578(T,A); rs848577(G,C)
ccdsGene name	CCDS41254.1
cytoBand name	1p36.21
EntrezGene GeneID	390999
EntrezGene Description	PRAME family member 12
EntrezGene Type of gene	protein-coding
Annovar Function	PRAMEF12:NM_001080830:exon2:c.T470C:p.M157T,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.0
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	O95522
dbNSFP Uniprot ID	PRA12_HUMAN
dbNSFP KGp1 AF	0.737637362637
dbNSFP KGp1 Afr AF	0.575203252033
dbNSFP KGp1 Amr AF	0.812154696133
dbNSFP KGp1 Asn AF	0.730769230769
dbNSFP KGp1 Eur AF	0.812664907652
dbSNP GMAF	0.2622
ESP Afr MAF	0.393327
ESP All MAF	0.263186
ESP Eur/Amr MAF	0.196512
ExAC AF	0.774

HNRNPCL1

dbSNP name	rs74055698(T,C)
ccdsGene name	CCDS30591.1
cytoBand name	1p36.21
EntrezGene GeneID	343069
EntrezGene Description	heterogeneous nuclear ribonucleoprotein C-like 1
EntrezGene Type of gene	protein-coding
Annovar Function	HNRNPCL1:NM_001013631:exon2:c.A764G:p.D255G,LOC649330:NM_001146181:exon1:c.A764G:p.D255G,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.0
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	O60812
dbNSFP Uniprot ID	HNRCL_HUMAN
dbNSFP KGp1 AF	0.311355311355
dbNSFP KGp1 Afr AF	0.400406504065
dbNSFP KGp1 Amr AF	0.290055248619
dbNSFP KGp1 Asn AF	0.344405594406
dbNSFP KGp1 Eur AF	0.238786279683
dbSNP GMAF	0.3118
ExAC AF	0.211

RSC1A1

dbSNP name	rs35040685(T,C); rs3766163(T,C); rs371024607(C,T)
ccdsGene name	CCDS161.1
cytoBand name	1p36.21
EntrezGene GeneID	84301
EntrezGene Symbol	DDI2
EntrezGene Description	DNA-damage inducible 1 homolog 2 (S. cerevisiae)
EntrezGene Type of gene	protein-coding
Annovar Function	RSC1A1:NM_006511:exon1:c.T2C:p.M1T,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.033
snpEff Effect	start_lost
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	high
dbNSFP Uniprot Acc	Q92681
dbNSFP Uniprot ID	RSCA1_HUMAN
dbNSFP KGp1 AF	0.00686813186813
dbNSFP KGp1 Afr AF	0.0243902439024
dbNSFP KGp1 Amr AF	0.00828729281768
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0
dbSNP GMAF	0.006887
ESP Afr MAF	0.021788
ESP All MAF	0.007381
ESP Eur/Amr MAF	0.0
ExAC AF	0.002246

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Prognathism;
[Mouth];
Thick, coarse lips;
[Teeth];
Natal teeth;
Malocclusion

SKELETAL:
[Hands];
Prominent interdigital folds;
Single transverse palmar creases;
First metacarpal hypoplasia;
Brachydactyly;
Single thumb creases;
[Feet];
First metatarsal hypoplasia;
Hypoplastic distal phalanges;
Brachydactyly

SKIN, NAILS, HAIR:
[Nails];
Nail dystrophy;
[Hair];
Trichodystrophy;
Straw-like fragile hair;
Irregular diameter of hair shaft with hypopigmentation and tendency
to fracture (light microscopy)

OMIM Title
*601966 REGULATORY SOLUTE CARRIER PROTEIN, FAMILY 1, MEMBER 1; RSC1A1
;;RS1

OMIM Description

DESCRIPTION

RSC1A1 is a negative regulator of Na(+)-dependent D-glucose transport
(Lambotte et al., 1996).

CLONING

Using primers based on the pig Rs1 sequence to amplify a probe from
human small intestine RNA, followed by screening a genomic library,
Lambotte et al. (1996) cloned human RSC1A1, which they called RS1. The
deduced 617-amino acid protein has a putative C-terminal transmembrane
domain. Pig and human RS1 share 74% overall identity, with 100% identity
in the C-terminal 42 amino acids that include the transmembrane domain.
Two of the 5 potential glycosylation sites in pig Rs1 are conserved in
human RS1. Lambotte et al. (1996) stated that human RS1 is expressed in
small intestine, kidney, and brain, and that pig Rs1 is expressed at the
extracellular side of brush border membranes of renal and intestinal
epithelial cells, where it colocalizes with the glucose transporter
SGLT1 (SLC5A1; 182380). In vitro-translated human RS1 had an apparent
molecular mass of 80 kD by SDS-PAGE.

GENE FUNCTION

By coexpression in Xenopus oocytes, Lambotte et al. (1996) found that
RS1 inhibited Na(+)-dependent D-glucose transport by SGLT1. Kinetic
analysis suggested that SGLT1 and RS1 interacted directly.

GENE STRUCTURE

Lambotte et al. (1996) determined that RSC1A1 is an intronless gene. The
5-prime UTR contains 2 Alu repeats, and the 3-prime UTR contains 1. The
5-prime UTR also contains a TATA box, at least 2 potential CAAT boxes,
binding sites for several transcription factors, including SP1 (189906),
AP1 (see 165160), and AP2 (TFAP2A; 107580), and 5 glucocorticoid
response elements.

MAPPING

Using FISH, Lambotte et al. (1996) mapped the RSC1A1 gene to chromosome
1p36.1.

UQCRHL

dbSNP name	rs66673012(A,T); rs7417535(T,C); rs61744357(C,T); rs61738972(C,T)
cytoBand name	1p36.21
EntrezGene GeneID	440567
snpEff Gene Name	RP11-169K16.7
EntrezGene Description	ubiquinol-cytochrome c reductase hinge protein-like
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	processed_pseudogene
snpEff Impact	modifier
dbSNP GMAF	0.141
ESP Afr MAF	0.337948
ESP All MAF	0.194141
ESP Eur/Amr MAF	0.120465
ExAC AF	0.123

KLHDC7A

dbSNP name	rs34109355(G,C); rs34976233(G,A); rs35013594(C,T); rs72944731(C,T); rs2992754(C,A); rs11261022(C,A); rs2992753(C,A); rs3007718(T,A); rs2992752(A,C); rs2992745(A,T); rs12061708(G,A); rs2992740(G,T); rs6667069(G,C); rs111688839(G,C); rs1889861(G,A); rs1889862(A,C); rs35259167(G,A); rs183779288(G,A); rs3007719(T,C); rs872355(G,A); rs708088(C,T)
ccdsGene name	CCDS185.2
CosmicCodingMuts gene	KLHDC7A
cytoBand name	1p36.13
EntrezGene GeneID	127707
EntrezGene Description	kelch domain containing 7A
EntrezGene Type of gene	protein-coding
Annovar Function	KLHDC7A:NM_152375:exon1:c.G145C:p.G49R,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.0113
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	Q5VTJ3
dbNSFP Uniprot ID	KLD7A_HUMAN
dbNSFP KGp1 AF	0.0975274725275
dbNSFP KGp1 Afr AF	0.0914634146341
dbNSFP KGp1 Amr AF	0.138121546961
dbNSFP KGp1 Asn AF	0.0506993006993
dbNSFP KGp1 Eur AF	0.117414248021
dbSNP GMAF	0.0978
ESP Afr MAF	0.096718
ESP All MAF	0.114029
ESP Eur/Amr MAF	0.122366
ExAC AF	0.108

LOC100506730

dbSNP name	rs6691134(T,G); rs3207843(G,A); rs55920101(C,T); rs67650707(T,C)
cytoBand name	1p36.13
EntrezGene GeneID	100506730
snpEff Gene Name	AKR7A3
EntrezGene Description	uncharacterized LOC100506730
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	upstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.1368

RNF186

dbSNP name	rs3820317(C,T); rs1541184(C,T); rs1541185(C,T)
cytoBand name	1p36.13
EntrezGene GeneID	54546
EntrezGene Description	ring finger protein 186
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	utr_3_prime
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.101

*OMIM Information*

OMIM Clinical Significance
Growth:
Failure to thrive

Neuro:
Mental and motor retardation

Facies:
Facial dysmorphism

Hair:
Abnormal hair

Teeth:
Abnormal teeth

Cardiac:
Myocardiopathy

Lab:
Placental S-adenosylhomocysteine hydrolase deficiency;
Hypermethioninemia

Inheritance:
Autosomal recessive

OMIM Title
*613754 RING FINGER PROTEIN 187; RNF187
;;RING DOMAIN AP1 COACTIVATOR 1; RACO1

OMIM Description

CLONING

Using a yeast 2-hybrid screen, Davies et al. (2010) identified RNF187,
which they called RACO1, as a JUN (165160)-interacting protein. The
deduced 235-amino acid protein, which is translated from a
nonconventional CTG initiation codon, has a calculated molecular mass of
26 kD. It contains an N-terminal C4HC3 RING domain. Western blot
analysis detected RACO1 expression in human HeLa and HCT116 cells and in
rat PC12 cells. In transfected HEK293 cells, RACO1 localized
predominantly to cytoplasm, with some RACO1 localized to nuclei.

GENE FUNCTION

Using a protein pull-down assay, Davies et al. (2010) confirmed that
endogenous rat Raco1 interacted with endogenous Jun. Mutation analysis
revealed that the short C-terminal region of human RACO1 bound to JUN,
and binding did not depend on JUN phosphorylation. Coexpression of RACO1
elevated JUN-dependent activation of a reporter gene. A constitutively
active form of MEKK1 (MAP3K1; 600982) enhanced JUN coactivation by
RACO1, whereas inhibition of MEK1 (MAP2K1; 176872) and MEK2 (MAP2K2;
601263) reduced JUN coactivation by RACO1. Davies et al. (2010) found
that RACO1 was polyubiquitinated on lys195 (K195), K223, or K224 near
its C terminus via autoubiquitination or via MEK1-dependent growth
factor signaling. Autoubiquitination tended to destabilize RACO1 and
involved the addition of ubiquitins linked together by their K48
residues. In contrast, ubiquitination via MEK1 signaling stabilized
RACO1 and involved ubiquitins linked by their K63 residues.
Overexpression of RACO1 increased proliferation of mouse fibroblasts,
promoted intestinal tumorigenesis in a mouse model, and cooperated with
oncogenic Ras (HRAS; 190020) in colonic hyperproliferation.

GENE STRUCTURE

Davies et al. (2010) determined that the RNF187 gene contains 4 coding
exons.

MAPPING

Hartz (2011) mapped the RNF187 gene to chromosome 1q42.13 based on an
alignment of the RNF187 sequence (GenBank GENBANK BC012758) with the
genomic sequence (GRCh37).

CAMK2N1

dbSNP name	rs11539080(T,G)
cytoBand name	1p36.12
EntrezGene GeneID	55450
EntrezGene Description	calcium/calmodulin-dependent protein kinase II inhibitor 1
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.01974

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal recessive

GROWTH:
[Weight];
Increased birth weight;
Obesity

HEAD AND NECK:
[Head];
Acrocephaly (rare);
Trigonocephaly (rare);
Brachycephaly (rare);
[Face];
Frontal bossing (rare);
Midface retrusion;
Retrognathia (rare);
[Ears];
Low-set ears;
Increased posterior angulation;
Protruding ears (rare);
Sensorineural hearing loss, mild (rare);
[Eyes];
Hypertelorism;
Epicanthal folds;
Upslanted palpebral fissures;
Nasolacrimal duct obstruction due to ectropion of lower eyelids (rare);
High-arched eyebrows;
Sparse eyebrows (rare);
[Nose];
Depressed nasal bridge;
Wide nasal bridge;
Anteverted nares;
Narrow nares (rare);
[Mouth];
Narrow palate;
High-arched palate;
[Teeth];
Multiple dental caries;
[Neck];
Short neck;
Webbed neck (rare)

CARDIOVASCULAR:
[Heart];
Dextrocardia;
Atrial septal defect (rare);
Tricuspid valve insufficiency (rare);
[Vascular];
Transposition of great vessels (rare);
Patent ductus arteriosus

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus carinatum;
Pectus excavatum;
[Breasts];
Widely spaced nipples;
Hypoplastic nipples;
Accessory nipples;
[Diaphragm];
Eventration of diaphragm;
Elevated right hemidiaphragm

ABDOMEN:
Situs inversus totalis (rare);
[External features];
Umbilical hernia (rare);
[Liver];
Left-sided liver (rare);
Central position of liver;
[Spleen];
Right-sided spleen (rare)

GENITOURINARY:
[External genitalia, male];
Small penis (rare);
Shawl scrotum (rare);
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
[Skull];
Craniosynostosis (primarily metopic, but may also involve coronal
or sagittal sutures);
[Pelvis];
Coxa vara (rare);
[Hands];
Brachydactyly;
Syndactyly, cutaneous;
Camptodactyly;
Broad thumbs;
Radially deviated thumbs;
Absent middle phalanges;
Postaxial polydactyly (rare);
Preaxial polydactyly, partial (rare);
Clinodactyly, 5th finger (rare);
[Feet];
Brachydactyly;
Syndactyly, cutaneous;
Preaxial polydactyly;
Absent middle phalanges;
Talipes equinovarus

SKIN, NAILS, HAIR:
[Skin];
Loose skin;
[Hair];
Sparse eyebrows

NEUROLOGIC:
[Central nervous system];
Developmental delay, variable severity

MISCELLANEOUS:
Variable features present

MOLECULAR BASIS:
Caused by mutation in the multiple epidermal growth factor-like domains-8
gene (MEGF8, 604267.0001)

OMIM Title
*614986 CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II INHIBITOR 1; CAMK2N1
;;CAMKII INHIBITORY PROTEIN, ALPHA;;
CAMKIIN-ALPHA

OMIM Description

DESCRIPTION

CAMK2N1 is an endogenous inhibitor of CAMKII (see 114078), a ubiquitous
serine/threonine protein kinase that phosphorylates nearly 40 different
proteins in response to intracellular calcium oscillations (Wang et al.,
2008).

CLONING

By searching a database for sequences similar to CAMKIIN-beta (CAMK2N2;
608721), followed by RT-PCR of bone marrow stromal cells, Wang et al.
(2008) cloned human CAMK2N1, which they called CAMKIIN-alpha. The
deduced 78-amino acid protein has a calculated molecular mass of 8.6 kD.
It has a 27-amino acid conserved inhibitory region in its C-terminal
half. PCR analysis detected variable CAMKII-alpha expression in all
human tissues examined except skeletal muscle. Highest expression was
detected in colon, small intestine, and ovary.

GENE FUNCTION

Wang et al. (2008) showed that endogenous human CAMKIIN-alpha interacted
directly with calcium-activated CAMKII and inhibited CAMKII activity.
CAMKIIN-alpha did not interact with inactive CAMKII. Wang et al. (2008)
observed an inverse correlation between expression of CAMKIIN-alpha and
severity of human colon adenocarcinomas. Overexpression of CAMKIIN-alpha
in human colon carcinoma cell lines inhibited cell growth by arresting
the cell cycle at the S phase, which correlated with phosphorylation and
accumulation of the cell cycle regulator p27 (CDKN1B; 600778).
CAMKIIN-alpha did not directly phosphorylate p27, but its inhibition of
CAMKII deactivated a MEK (see 176872)/ERK (see 176948) signaling pathway
required to inhibit p27 phosphorylation and induce proteasome-dependent
degradation of nonphosphorylated p27. Deletion analysis revealed that
the C-terminal inhibitory domain of CAMKIIN-alpha was required for all
of its cellular effects.

MAPPING

Hartz (2012) mapped the CAMK2N1 gene to chromosome 1p36.12 based on an
alignment of the CAMK2N1 sequence (GenBank GENBANK DB475389) with the
genomic sequence (GRCh37).

FAM43B

dbSNP name	rs74058407(A,G); rs3795509(T,A)
cytoBand name	1p36.12
EntrezGene GeneID	163933
EntrezGene Description	family with sequence similarity 43, member B
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	utr_3_prime
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.225

EPHA8

dbSNP name	rs209736(T,C); rs209735(C,T); rs139657800(G,A); rs209751(C,G); rs209750(C,A); rs115366026(G,A); rs209749(A,C); rs209748(A,G); rs60615053(C,T); rs56796524(C,T); rs61767285(A,G); rs137874706(C,T); rs209746(T,C); rs185704683(C,T); rs145910820(G,A); rs138469609(G,A); rs209741(T,C); rs59478017(G,A); rs115131664(C,G); rs148361941(C,T); rs150436231(C,T); rs187291359(G,A); rs761398(T,A); rs116708974(T,C); rs11580191(C,T); rs150553424(G,A); rs72875426(C,T); rs114947354(G,C); rs649754(A,C); rs72651336(C,T); rs146469008(A,G); rs74611858(A,G); rs492053(A,G); rs115328469(A,G); rs189979612(A,G); rs115487004(G,A); rs56403640(C,T); rs570220(G,A); rs116335188(G,T); rs586823(A,G); rs11581616(C,T); rs682187(T,C); rs682118(C,A); rs11582171(C,A); rs667566(A,G); rs482156(G,A); rs665395(C,G); rs567711(A,G); rs10917259(A,G); rs10917260(C,T); rs651637(A,G); rs639519(T,C); rs537426(A,G); rs147744273(A,G); rs12066127(G,A); rs10917261(G,T); rs10917262(G,A); rs624005(A,G); rs3767556(G,T); rs609125(T,C); rs606002(T,C); rs11584845(C,G); rs521570(A,T); rs10917263(G,A); rs189166920(C,T); rs10917264(C,T); rs671485(T,C); rs140375453(C,T); rs145472393(G,C); rs67275312(T,A); rs61767310(A,T); rs147513349(C,T); rs72651342(C,A); rs61767311(G,A); rs209696(C,T); rs11802802(G,A); rs61767313(C,T); rs61767314(G,A); rs11801773(A,C); rs11802120(T,C); rs209693(T,G); rs116492046(T,G); rs12071465(G,A); rs209692(G,A); rs209691(G,A); rs209690(G,A); rs1005675(C,T); rs209689(A,G); rs11585855(C,A); rs11582356(G,A); rs61767315(G,A); rs72651347(G,A); rs141239679(G,T); rs12030727(T,C); rs12404556(T,C); rs664340(C,G); rs663002(C,A); rs11805067(G,A); rs11808747(C,A); rs72651352(G,A); rs209700(A,G); rs209699(A,G); rs209698(A,G); rs209697(A,G); rs114594938(C,T)
ccdsGene name	CCDS225.1
cytoBand name	1p36.12
EntrezGene GeneID	2046
EntrezGene Description	EPH receptor A8
EntrezGene Type of gene	protein-coding
Annovar Function	EPHA8:NM_020526:exon14:c.G2476A:p.V826M,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.7182
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP KGp1 AF	0.0
dbNSFP KGp1 Afr AF	0.0
dbNSFP KGp1 Amr AF	0.0
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0
dbSNP GMAF	0.0
ESP Afr MAF	0.000227
ESP All MAF	0.000923
ESP Eur/Amr MAF	0.001279
ExAC AF	0.0006831

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Somatic mutation

GROWTH:
[Other];
Hemihypertrophy;
Generalized, unilateral or localized disproportionate overgrowth of
any tissue

HEAD AND NECK:
[Head];
Macrocephaly;
Hyperostoses of calvaria, facial bones, and mandible;
Dolichocephaly;
[Face];
Long face;
[Eyes];
Epibulbar dermoids;
Downslanting palpebral fissures;
Ptosis;
[Nose];
Low nasal bridge;
Wide or anteverted nostrils;
[Mouth];
Open mouth

CARDIOVASCULAR:
[Vascular];
Capillary malformations;
Venous malformations;
Lymphatic malformations;
Deep vein thrombosis

RESPIRATORY:
[Lung];
Lung cysts

ABDOMEN:
[Spleen];
Splenomegaly

SKELETAL:
[Spine];
Megaspondylodysplasia;
Kyphoscoliosis;
Spinal stenosis from angular kyphoscoliosis;
[Limbs];
Overgrown long bones;
Thin cortices

SKIN, NAILS, HAIR:
[Skin];
Cerebriform connective tissue nevus;
Lymphangioma;
Lipoma;
Lipohypoplasia;
Epidermal nevi;
Hypertrophy of skin of soles;
Depigmentation/hyperpigmentation;
Hemangiomata, especially thorax and upper abdomen;
HISTOLOGY:;
Highly collagenized connective tissue;
Acanthosis;
Hyperkeratosis;
Dermal hypoplasia

NEUROLOGIC:
[Central nervous system];
Brain malformations;
Spinal cord compression by tumor infiltration;
Mental retardation, moderate (in some patients)

NEOPLASIA:
Ovarian cystadenoma;
Parotid monomorphic adenoma

MISCELLANEOUS:
Onset in infancy;
Sporadic occurrence;
Mosaic distribution of lesions;
Progressive disorder

MOLECULAR BASIS:
Caused by somatic mutation in the V-AKT murine thymoma viral oncogene
homolog 1 gene (AKT1, 164730.0001)

OMIM Title
*176945 EPHRIN RECEPTOR EphA8; EPHA8
;;EPH- AND ELK-RELATED KINASE; EEK;;
PROTEIN TYROSINE KINASE EEK;;
HEK3

OMIM Description

CLONING

Chan and Watt (1991) identified human and rat DNAs encoding 2 novel
members of the EPH subclass of putative receptor protein-tyrosine
kinases. Rat cDNA clones encoding EEK (EPH- and ELK-related kinase) were
isolated from a brain cDNA library probed with DNA encoding the kinase
region of the insulin receptor-related receptor (INSRR; 147671). The EEK
protein was predicted to contain all the amino acid residues conserved
in the catalytic domains of protein-tyrosine kinases and was most
similar to 2 putative receptor protein-tyrosine kinases of the EPH
subclass, ELK (EPHB1; 600600) and EPH, showing 69 and 57% identity,
respectively. Human genomic DNAs, encoding part of EEK as well as
another putative protein tyrosine kinase most similar to ELK (90%) and
symbolized ERK (EPHB2; 600997) for ELK-related kinase, were isolated and
partially characterized. In Northern blot analysis of rat RNA, DNAs
encoding rat EEK and human ERK hybridized to transcripts most abundant
in brain and lung, respectively. These 2 new members of the EPH subclass
of receptor protein-tyrosine kinases, EEK and ERK, may therefore have
tissue-specific functions distinct from those of the other EPH family
members.

MAPPING

Chan and Watt (1991) mapped the EPHA8 AND EPHB1 genes to chromosome 1.

GENE FAMILY

The EPH and EPH-related receptors comprise the largest subfamily of
receptor protein-tyrosine kinases. They have been implicated in
mediating developmental events, particularly in the nervous system.
Receptors in the Eph subfamily typically have a single kinase domain and
an extracellular region containing a Cys-rich domain and 2 fibronectin
type III repeats. The ligands for Eph receptors have been named ephrins
by the Eph Nomenclature Committee (1997). Based on their structures and
sequence relationships, ephrins are divided into the ephrin-A (EFNA)
class, which are anchored to the membrane by a
glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class,
which are transmembrane proteins. The Eph family of receptors are
divided into 2 groups based on the similarity of their extracellular
domain sequences and their affinities for binding ephrin-A and ephrin-B
ligands. The Eph Nomenclature Committee (1997) proposed that Eph
receptors interacting preferentially with ephrin-A proteins be called
EphA and Eph receptors interacting preferentially with ephrin-B proteins
be called EphB.

ANIMAL MODEL

Park et al. (1997) generated mice homozygous for a mutation that
disrupts the gene encoding EPHA8, a member of the Eph family of tyrosine
proteinase receptors. EphA8 -/- mice developed to term, were fertile,
and did not display obvious anatomical or physiologic defects. The mouse
EphA8 gene is expressed primarily in a rostral to caudal gradient in the
developing tectum. Axonal tracing experiments revealed that in these
mutant mice, axons from a subpopulation of tectal neurons located in the
superficial layers of the superior colliculus did not reach targets
located in the contralateral inferior colliculus. Moreover, EphA8-null
animals displayed an aberrant ipsilateral axonal tract that projected to
the ventral region of the cervical spinal cord. Retrograde labeling
revealed that these abnormal projections originated from a small
subpopulation of superior colliculus neurons that normally express the
EPHA8 gene. Park et al. (1997) suggested that EPHA8 receptors play a
role in axonal pathfinding during development of the mammalian nervous
system.

HTR1D

dbSNP name	rs623988(C,T); rs137884002(G,T)
cytoBand name	1p36.12
EntrezGene GeneID	3352
EntrezGene Description	5-hydroxytryptamine (serotonin) receptor 1D, G protein-coupled
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.3485

*OMIM Information*

OMIM Clinical Significance

Skin:
Seborrheic keratoses;
Congenital seborrheic verrucae

Inheritance:
Autosomal dominant form

OMIM Title
*182133 5-@HYDROXYTRYPTAMINE RECEPTOR 1D; HTR1D
;;SEROTONIN 5-HT-1D RECEPTOR;;
5-@HYDROXYTRYPTAMINE RECEPTOR 1D-ALPHA; HTR1DA;;
RDC4

OMIM Description
The serotonin 1D receptor was initially characterized by radioligand
binding procedures using membranes derived from bovine caudate nucleus.
The 5-HT-1D receptor is known to be a G protein-coupled receptor.
Sumatriptan, an agent effective in the treatment of acute migraine, is
the only ligand yet identified that is selective for the 5-HT-1D
receptor. Weinshank et al. (1992) reported the cloning, deduced amino
acid sequences, pharmacologic properties, and second-messenger coupling
of a pair of human 5-HT-1D receptor genes, which they designated alpha
and beta due to their strong similarities. Both genes have no introns in
their coding regions, are expressed in the human cerebral cortex, and
can couple to inhibition of adenylate cyclase activity. Their
pharmacologic binding properties match closely those of human, bovine,
and guinea pig 5-HT-1D sites. Libert et al. (1991) obtained cDNA clones
encoding 4 receptors of the G protein-coupled receptor family by
selective amplification and cloning from thyroid cDNA. One of these
clones, termed RDC4 by them, showed close structural similarity with the
serotonin 5HT1A receptor (109760). By in situ hybridization, they
demonstrated that the gene (HTR1D) is located on chromosome 1 at
1p36.3-p34.3. By Southern blot analysis of a hybrid cell panel, Jin et
al. (1992) showed that the HTR1D gene is located on chromosome 1. Wilkie
et al. (1993) showed that the homologous gene in the mouse is located on
chromosome 4.

LOC100996511

dbSNP name	rs658636(A,G); rs12096254(C,T); rs148647119(A,G); rs181424467(G,A); rs672904(C,T); rs594228(T,A); rs143637197(T,A)
cytoBand name	1p36.12
EntrezGene GeneID	100996511
EntrezGene Description	uncharacterized LOC100996511
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	intergenic
snpEff Functional Class	none
snpEff Impact	modifier
dbSNP GMAF	0.06657

C1orf213

dbSNP name	rs638722(T,C); rs754984(C,G)
cytoBand name	1p36.12
EntrezGene GeneID	148898
EntrezGene Description	chromosome 1 open reading frame 213
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	processed_transcript
snpEff Impact	modifier
dbSNP GMAF	0.2553
ESP Afr MAF	0.295809
ESP All MAF	0.215836
ESP Eur/Amr MAF	0.179368
ExAC AF	0.205

E2F2

dbSNP name	rs12026768(G,T); rs111903743(T,A); rs12027599(G,A); rs3820028(G,A); rs147131506(C,T); rs3218211(A,G); rs2075993(A,G); rs3218205(T,C); rs3218203(C,G); rs147537360(G,A); rs2282720(A,G); rs2811972(T,C); rs3218192(G,T); rs3218186(G,T); rs114788023(C,T); rs2075994(C,T); rs3218181(C,T); rs2811974(C,G); rs3218177(G,A); rs3218175(C,T); rs3218173(A,C); rs12041537(C,T); rs144666986(C,T); rs3218172(G,T); rs2075995(C,A); rs116694174(G,A); rs2075996(C,G); rs2038026(T,C); rs2038027(A,G); rs2282724(C,T); rs2236853(C,A)
ccdsGene name	CCDS236.1
cytoBand name	1p36.12
EntrezGene GeneID	1870
EntrezGene Description	E2F transcription factor 2
EntrezGene Type of gene	protein-coding
Annovar Function	E2F2:NM_004091:exon4:c.C605T:p.T202I,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.6601
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	Q14209
dbNSFP Uniprot ID	E2F2_HUMAN
dbNSFP KGp1 AF	0.0018315018315
dbNSFP KGp1 Afr AF	0.0
dbNSFP KGp1 Amr AF	0.00276243093923
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.00395778364116
dbSNP GMAF	0.001837
ESP Afr MAF	0.001362
ESP All MAF	0.00346
ESP Eur/Amr MAF	0.004535
ExAC AF	0.002919

*OMIM Information*

OMIM Clinical Significance

Skin:
Angiokeratoma corporis diffusum

Vascular:
Arteriovenous fistulas

Limbs:
Asymmetric hypertrophy and hyperhidrosis of a leg

Misc:
Onset in infancy and early adulthood;
No systemic symptoms

Radiology:
Arteriographic demonstration of multiple arteriovenous fistulas

Inheritance:
Autosomal dominant

OMIM Title
*600426 E2F TRANSCRIPTION FACTOR 2; E2F2

OMIM Description
See E2F1 (189971).

CLONING

Ivey-Hoyle et al. (1993) cloned a cDNA from a HeLa cell library using a
probe containing the DNA-binding domain of E2F1. The cDNA, designated
E2F2, has overall amino acid sequence similarity to E2F1 of 46%. The
same cDNA and corresponding genomic region was cloned by Lees et al.
(1993). Lees et al. (1993) also showed that expressed E2F2 bound to both
the E2F DNA recognition sites and to the RB1 protein (614041).

GENE FUNCTION

MYC (190080) induces transcription of the E2F1, E2F2, and E2F3 (600427)
genes. Using primary mouse embryo fibroblasts deleted for individual E2f
genes, Leone et al. (2001) showed that MYC-induced S phase and apoptosis
requires distinct E2F activities. The ability of Myc to induce S phase
was impaired in the absence of either E2f2 or E2f3 but not E2f1 or E2f4
(600659). In contrast, the ability of Myc to induce apoptosis was
markedly reduced in cells deleted for E2f1 but not E2f2 or E2f3. The
authors proposed that the induction of specific E2F activities is an
essential component in the MYC pathways that control cell proliferation
and cell fate decisions.

The retinoblastoma tumor suppressor (Rb) pathway is believed to have a
critical role in the control of cellular proliferation by regulating E2F
activities. E2F1, E2F2, and E2F3 belong to a subclass of E2F factors
thought to act as transcriptional activators important for progression
through the G1/S transition. Wu et al. (2001) used a conditional gene
targeting approach to demonstrate that combined loss of these 3 E2F
factors severely affects E2F target expression and completely abolishes
the ability of mouse embryonic fibroblasts to enter S phase, progress
through mitosis, and proliferate. Loss of E2F function results in
elevation of CIP1 (116899) protein, leading to a decrease in
cyclin-dependent kinase activity and Rb phosphorylation. Wu et al.
(2001) concluded that these findings suggested a function for this
subclass of E2F transcriptional activators in a positive feedback loop,
through downmodulation of CIP1, that leads to the inactivation of
Rb-dependent repression and S phase entry. By targeting the entire
subclass of E2F transcriptional activators, Wu et al. (2001) provided
direct genetic evidence for their essential role in cell cycle
progression, proliferation, and development. Wu et al. (2001) initially
generated and interbred E2f1, E2f2, and E2f3 mutant mice, and found that
although mice null for E2f1 and E2f2 were viable and developed to
adulthood, mice null for E2f1 and E2f3 or E2f2 and E2f3 died early
during embryonic development, at or just before embryonic day 9.5,
pointing to a central role for E2F3 in mouse development.

Funke-Kaiser et al. (2003) identified 5 polymorphisms in the ECE1 gene
(600423), a candidate for human blood pressure regulation, among a
cohort of 704 European hypertensive patients. Electrophoretic mobility
shift assays revealed the specific binding of E2F2 to ECE1b promoter
sequences containing either allele of the C-338A polymorphism
(600423.0002), with the -338A allele being associated with an increased
affinity to E2F2 compared with -338C. The authors proposed a link
between the cell cycle-associated E2F family and blood pressure
regulation via a component of the endothelin system.

To address the function of E2F1, E2F2, and E2F3 in normal mammalian
cells in vivo, Chen et al. (2009) focused on the mouse retina, which is
a relatively simple central nervous system component that can be
manipulated genetically without compromising viability and has provided
considerable insight into development and cancer. The authors showed
that unlike fibroblasts, E2f1-, E2f2-, and E2f3-null retinal progenitor
cells or activated Muller glia can divide. Chen et al. (2009) attributed
this effect to functional interchangeability with Mycn (164840).
However, loss of activating E2fs caused downregulation of the p53
(191170) deacetylase Sirt1 (604479), p53 hyperacetylation, and elevated
apoptosis, establishing a novel E2f-Sirt1-p53 survival axis in vivo.
Chen et al. (2009) concluded that activating E2fs are not universally
required for normal mammalian cell division, but have an unexpected
prosurvival role in development.

Using a panel of tissue-specific cre-transgenic mice and conditional E2f
alleles, Chong et al. (2009) examined the effects of E2f1, E2f2, and
E2f3 triple deficiency in murine embryonic stem cells, embryos, and
small intestines. They showed that in normal dividing progenitor cells,
E2f1-3 function as transcriptional activators, but are dispensable for
cell division and instead are necessary for cell survival. In
differentiating cells E2f1-3 function in a complex with Rb (614041) as
repressors to silence E2f targets and facilitate exit from the cell
cycle. The inactivation of Rb in differentiating cells resulted in a
switch of E2f1-3 from repressors to activators, leading to the
superactivation of E2f-responsive targets and ectopic cell divisions.
Loss of E2f1-3 completely suppressed these phenotypes caused by Rb
deficiency. Chong et al. (2009) concluded that their work contextualizes
the activator versus repressor functions of E2f1-3 in vivo, revealing
distinct roles in dividing versus differentiating cells and in normal
versus cancer-like cell cycles.

MAPPING

Lees et al. (1993) mapped the E2F2 gene to 1p36 by fluorescence in situ
hybridization.

ANIMAL MODEL

Iglesias et al. (2004) generated mice deficient in both E2f1 (189971)
and E2f2. The mice developed nonautoimmune insulin-deficient diabetes
and exocrine pancreatic dysfunction characterized by endocrine and
exocrine cell dysplasia and a reduction in the number and size of acini
and islets, which were replaced by ductal structures and adipose tissue.
Mutant pancreatic cells exhibited increased rates of DNA replication but
also of apoptosis, resulting in severe pancreatic atrophy. The
expression of genes involved in DNA replication and cell cycle control
was upregulated in the E2f1/E2f2 compound mutant pancreas. Iglesias et
al. (2004) suggested that E2F1/E2F2 activity negatively controls growth
of mature pancreatic cells and is necessary for the maintenance of
differentiated pancreatic phenotypes in the adult.

ID3

dbSNP name	rs1050096(G,A); rs2920(T,C); rs2067054(C,G); rs11574(T,C); rs2067053(T,C); rs61749352(C,G); rs142720912(C,G)
ccdsGene name	CCDS237.1
cytoBand name	1p36.12
EntrezGene GeneID	3399
EntrezGene Description	inhibitor of DNA binding 3, dominant negative helix-loop-helix protein
EntrezGene Type of gene	protein-coding
Annovar Function	ID3:NM_002167:exon1:c.G256C:p.E86Q,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.8474
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	Q02535
dbNSFP Uniprot ID	ID3_HUMAN
dbNSFP KGp1 AF	0.00641025641026
dbNSFP KGp1 Afr AF	0.0243902439024
dbNSFP KGp1 Amr AF	0.00552486187845
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0
dbSNP GMAF	0.006428
ESP Afr MAF	0.023604
ESP All MAF	0.00815
ESP Eur/Amr MAF	0.000233
ExAC AF	2.740e-03,1.626e-05

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Frontal lobe dementia;
Language impairment;
Word-finding difficulties;
Decrease in abstract thinking;
Motor symptoms may be present;
Parkinsonism;
Amyotrophic lateral sclerosis;
Cortical and subcortical neuronal loss in the frontal and temporal
regions;
Tau-positive inclusions may be found;
Ubiquitin-positive inclusions;
Primitive reflexes (palmomental, snout, glabellar);
[Behavioral/psychiatric manifestations];
Personality changes;
Lack of motivation;
Inappropriate laughter;
Apathy;
Irritability;
Disinhibition;
Kluver-Bucy syndrome;
Inappropriate sexual behavior;
Hyperphagia;
Hyperoralia

MISCELLANEOUS:
Mean age at onset 45 years;
Highly variable phenotype that includes several subtypes (see, e.g.,
607485, 601104);
Genetic heterogeneity (see, e.g., 600795, 105550);
Most cases do not have mutations in the MAPT gene, but map to chromosome
17q

MOLECULAR BASIS:
Caused by mutation in the microtubule-associated tau protein gene
(MAPT, 157140.0001);
Caused by mutation in the presenilin-1 gene (PSEN1, 104311.0023)

OMIM Title
*600277 INHIBITOR OF DNA BINDING 3; ID3
;;HEIR1

OMIM Description

DESCRIPTION

Members of the ID family of helix-loop-helix (HLH) proteins lack a basic
DNA-binding domain and inhibit transcription through formation of
nonfunctional dimers that are incapable of binding to DNA.

CLONING

Ellmeier et al. (1992) isolated a novel human gene encoding a
helix-loop-helix protein by molecular cloning of chromosome
1p36-specific CpG islands. Initially termed HEIR1, the ID3 gene was
localized to the neuroblastoma consensus deletion region, 1p36.2-p36.12.
Its predicted protein was 95.8% identical to the mouse HLH462 protein
and had clear homology to the mouse Id and Drosophila emc proteins. The
gene was expressed at high abundance in adult lung, kidney, and adrenal
medulla, but not in adult brain. Despite prominent HEIR1 expression in
adrenal medulla, which is a prime target for neuroblastomas, 10 of 12
neuroblastoma-derived cell lines showed very low levels of HEIR1 mRNA.
Low HEIR1 expression was generally found in tumor cell lines with NMYC
(164840) overexpression, whereas the 2 cell lines displaying high HEIR1
levels did not overexpress NMYC. Mutually exclusive expression of the 2
genes was also found by in situ hybridization in developing mouse
tissues, particularly in the forebrain neuroectoderm. Ellmeier et al.
(1992) concluded that HEIR1 expression is reduced specifically in the
majority of neuroblastomas and suggested an inverse correlation between
HEIR1 and NMYC expression in these tumors and in embryonic development.

GENE FUNCTION

ID3 is an inhibitor of E proteins, such as E2A (147141). By Northern and
Western blot analysis, Kee et al. (2001) showed that transforming growth
factor-beta (190180) in mouse rapidly induced transient Id3 expression
in B-lymphocyte precursors. This induction involved activation of the
SMAD (see 602932) transcription factor pathway.

Kaplan et al. (2005) demonstrated that bone marrow-derived hematopoietic
progenitor cells that express VEGFR1 (605070) home to tumor-specific
premetastatic sites and form cellular clusters before the arrival of
tumor cells. Preventing VEGFR1 function using antibodies or by the
removal of VEGFR1-positive cells from the bone marrow of wildtype mice
abrogated the formation of these premetastatic clusters and prevented
tumor metastasis, whereas reconstitution with selected Id3-competent
VEGFR1-positive cells established cluster formation and tumor metastasis
in Id3 knockout mice. Kaplan et al. (2005) also showed that
VEGFR1-positive cells express VLA4, also known as integrin
alpha-4-beta-1 (see 192975), and that tumor-specific growth factors
upregulate fibronectin (135600), a VLA4 ligand, in resident fibroblasts,
providing a permissive niche for incoming tumor cells. Conditioned media
obtained from distinct tumor types with unique patterns of metastatic
spread redirected fibronectin expression and cluster formation, thereby
transforming the metastatic profile. Kaplan et al. (2005) concluded that
their findings demonstrated a requirement for VEGFR1-positive
hematopoietic progenitors in the regulation of metastasis, and suggest
that expression patterns of fibronectin and
VEGFR1-positive-VLA4-positive clusters dictate organ-specific tumor
spread.

GENE STRUCTURE

Deed et al. (1994) reported a comparison of the ID3 gene with ID1
(600349) and ID2 (600386) that showed a highly conserved protein-coding
gene organization consistent with evolution from a common ancestral
gene.

Yeh and Lim (2000) determined that both the human and mouse genes
contain 3 exons spanning about 1.5 kb.

MAPPING

By using a YAC clone of ID3 for fluorescence in situ hybridization, Deed
et al. (1994) mapped the ID3 gene to 1p36.1.

White et al. (1995) excluded ID3 as a candidate for the neuroblastoma
suppressor gene because it lies outside the loss of heterozygosity
region revealed by neuroblastoma studies (see 256700).

MOLECULAR GENETICS

Using whole-genome, whole-exome, and transcriptome sequencing of 4
prototypical Burkitt lymphomas (113970) with immunoglobulin gene (IG;
see 147220)-MYC translocation (190080), Richter et al. (2012) identified
7 recurrently mutated genes. One of these genes, ID3, mapped to a region
of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36
of 53 molecularly defined Burkitt lymphomas (68%) carried potentially
damaging mutations of ID3. These were strongly enriched at somatic
hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the
IG-MYC translocation (13%) carried ID3 mutations. Richter et al. (2012)
concluded that their findings suggested that cooperation between ID3
inactivation and IG-MYC translocation is a hallmark of Burkitt
lymphomagenesis.

Love et al. (2012) described the first completely sequenced genome from
a Burkitt lymphoma tumor and germline DNA from the same affected
individual, and further sequenced the exomes of 59 Burkitt lymphoma
tumors and compared them to sequenced exomes from 94 diffuse large
B-cell lymphoma tumors. Love et al. (2012) identified 70 genes that were
recurrently mutated in Burkitt lymphomas, including ID3, GNA13 (604406),
RET (164761), PIK3R1 (171833), and the SWI/SNF genes ARID1A (603024) and
SMARCA4 (603254). Love et al. (2012) stated that their data implicate a
number of genes in cancer for the first time, including CCT6B (610730),
SALL3 (605079), FTCD (606806), and PC (608786). ID3 mutations occurred
in 34% of Burkitt lymphomas and not in diffuse large B-cell lymphomas
(DLBCLs). Love et al. (2012) showed experimentally that ID3 mutations
promote cell cycle progression and proliferation.

ANIMAL MODEL

Id proteins may control cell differentiation by interfering with DNA
binding of transcription factors. Lyden et al. (1999) demonstrated that
the targeted disruption of Id1 (600349) and Id3 in mice results in
premature withdrawal of neuroblasts in the cell cycle and expression of
neural-specific differentiation markers. Lyden et al. (1999) crossed Id1
+/- and Id3 +/- mice. Offspring lacking 1 to 3 Id alleles in any
combination were indistinguishable from wildtype, but no animals lacking
all 4 Id alleles were born. The Id1-Id3 double knockout mice displayed
vascular malformations in forebrain and absence of branching and
sprouting of blood vessels in the neuroectoderm. As angiogenesis both in
the brain and in tumors requires invasion of avascular tissue by
endothelial cells, Lyden et al. (1999) examined Id knockout mice for
their ability to support the growth of tumor xenografts. Three different
tumors failed to grow and/or metastasize in Id1 +/- Id3 -/- mice, and
any tumor growth present showed poor vascularization and extensive
necrosis. Lyden et al. (1999) concluded that Id genes are required to
maintain the timing of neuronal differentiation in the embryo and
invasiveness of the vasculature. Because the Id genes are expressed at
very low levels in adults, they make attractive targets for
antiangiogenic drug design. Lyden et al. (1999) also concluded that the
premature neuronal differentiation in Id1-Id3 double knockout mice
indicates that ID1 or ID3 is required to block the precisely timed
expression and activation of positively acting bHLH proteins during
murine development.

Pan et al. (1999) found that Id3-deficient mice had no overt
abnormalities but had compromised humoral immunity. After immunization
with T cell-dependent or T cell-independent antigens, the responses of
Id3-deficient mice were attenuated and severely impaired, respectively.
T-cell proliferative responses appeared to be intact, but IFNG
expression may have been impaired. The defect in B-cell proliferation
could be rescued by ectopic expression of Id1.

In the developing heart, Id1, Id2 (600386), and Id3 are detected in the
endocardial cushion mesenchyme from embryonic days 10.5 through 16.5,
but Id4 (600581) is absent. Fraidenraich et al. (2004) showed that Id1
to Id3 are also expressed in the epicardium and endocardium but are
absent in the myocardium. Id1 to Id3 expression becomes confined in the
leaflets of the cardiac valves as the atrioventricular endocardial
cushion tissue myocardializes. Id1 and Id3 expression persists in the
cardiac valves, endocardium, endothelium, and epicardium at postnatal
day 7. Fraidenraich et al. (2004) found that double and triple Id
knockout embryos displayed severe cardiac defects and died at
midgestation. Embryo size was reduced by 10 to 30%. Knockout embryos
displayed ventricular septal defects associated with impaired
ventricular trabeculation and thinning of the compact myocardium.
Trabeculae had disorganized sheets of myocytes surrounded by
discontinuous endocardial cell lining. Cell proliferation in the
myocardial wall was defective. Fraidenraich et al. (2004) showed that
midgestation lethality of embryos was rescued by the injection of 15
wildtype embryonic stem (ES) cells into mutant blastocysts. Myocardial
markers altered in Id mutant cells were restored to normal throughout
the chimeric myocardium. Intraperitoneal injection of ES cells into
female mice before conception also partially rescued the cardiac
phenotype with no incorporation of ES cells. Insulin-like growth
factor-1 (IGF1; 147440), a long-range secreted factor, in combination
with Wnt5a (164975), a locally secreted factor, were thought likely to
account for complete reversion of the cardiac phenotype. Fraidenraich et
al. (2004) concluded that ES cells have the potential to reverse
congenital defects through Id-dependent local and long-range effects in
a mammalian embryo.

Li et al. (2004) observed that Id3 -/- mice had difficulty maintaining
fully opened eyelids beginning at 6 months and progressing with age.
Histologic and electron microscopic analysis of mutant mice revealed
lymphocytic infiltration in the lachrymal and salivary glands in the
absence of infection, and the CD4 (186940) and CD8 (see 186910) T cells
and B cells in the infiltrates expressed both Ifng (147570) and Il4
(147780). Id3 -/- mice showed reduced tear and saliva secretion,
suggesting a disease similar to Sjogren syndrome (270150). ELISA
analysis detected both anti-SSA (SSA1; 109092) and anti-SSB (109090)
autoantibodies in Id3 -/- mice after 1 year of age. Bone marrow
transplant experiments showed that the phenotype was mediated by
hemopoietic cells, and adoptive transfer analysis attributed a dominant
role to Id3 -/- T lymphocytes. Elimination of T cells and neonatal
thymectomy demonstrated that the tear and saliva secretion defect
required sustained production of thymic T cells. Li et al. (2004)
concluded that ID3-mediated T-cell development is connected to
autoimmune disease, and they proposed that the Id3 -/- mouse is a model
for primary Sjogren syndrome.

By selective deletion of both Id2 and Id3 at the pre-T-cell receptor
(TCR) and gamma/delta TCR checkpoints in mice, Li et al. (2013) observed
a partial block at the pre-TCR checkpoint as well as increased
production of innate gamma/delta T cells. In addition, the double
deletion resulted in a dramatic increase in invariant NKT (iNKT) cells.
Li et al. (2013) proposed that there are opposing roles for ID genes in
regulating the alpha/beta and innate gamma/delta lineages. They
concluded that there is a dosage-dependent mechanism for ID genes in
repressing the fate of innate-like gamma/delta T cells versus iNKT cells
during T-cell development.

LOC644961

dbSNP name	rs57922300(A,G); rs80088173(A,G); rs79070316(A,G); rs55663650(G,A)
ccdsGene name	CCDS297.2
cytoBand name	1p36.11
EntrezGene GeneID	644961
snpEff Gene Name	TMEM222
EntrezGene Description	actin, gamma 1 pseudogene
EntrezGene Type of gene	pseudo
Annovar Region type	ncRNA_exonic
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.1166

ATPIF1

dbSNP name	rs2232720(G,T); rs6686978(G,A); rs8559(A,G); rs9508(A,G); rs115245379(G,T)
ccdsGene name	CCDS319.1
cytoBand name	1p35.3
EntrezGene GeneID	93974
EntrezGene Description	ATPase inhibitory factor 1
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
dbNSFP LR score	0.0713
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP KGp1 AF	0.0178571428571
dbNSFP KGp1 Afr AF	0.00609756097561
dbNSFP KGp1 Amr AF	0.0110497237569
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0422163588391
dbSNP GMAF	0.01791
ESP Afr MAF	0.006358
ESP All MAF	0.021766
ESP Eur/Amr MAF	0.029658
ExAC AF	0.023

COL16A1

dbSNP name	rs1061392(C,A); rs114540619(G,A); rs3817398(T,C); rs16834643(T,C); rs142404474(G,A); rs945215(T,C); rs7545321(A,G); rs16834646(G,C); rs56074668(T,C); rs60364385(C,T); rs16834652(A,G); rs60694879(G,A); rs16834658(A,C); rs10914462(A,G); rs11807560(C,T); rs41263967(C,T); rs72887309(G,C); rs2271928(G,A); rs1568396(C,G); rs12032291(A,G); rs185012160(C,T); rs76756188(G,T); rs1356803(C,G); rs10914463(C,T); rs10914464(G,A); rs57844188(G,A); rs16834664(G,A); rs2292988(C,T); rs2271929(C,G); rs72887317(T,C); rs7512805(C,T); rs147635174(C,G); rs6425778(T,A); rs7525091(A,G); rs7537646(G,A); rs2292989(A,G); rs1474182(G,A); rs78958534(G,A); rs72887321(A,G); rs35986497(G,A); rs909002(C,T); rs4949456(G,A); rs4949457(C,T); rs10798883(C,T); rs2292993(C,T); rs1123948(C,T); rs6425779(T,C); rs7540151(G,C); rs4949458(T,G); rs4949459(G,T); rs4949460(G,A); rs1568397(A,G); rs4949461(C,T); rs11590964(C,T); rs2297684(C,T); rs4949462(A,G); rs10737358(A,G); rs78189411(C,G); rs375798080(A,C); rs72887330(A,G); rs4568876(C,T); rs182398334(A,G); rs113905439(C,T); rs376511262(G,A); rs2297682(T,C); rs75020493(G,A); rs11589051(G,A); rs11589456(G,A); rs6425780(G,T); rs2297681(G,A); rs10914467(G,A); rs10798884(A,T); rs2297676(T,C); rs116200113(G,A); rs3818788(T,C); rs117922701(C,T); rs74063964(C,T); rs2275097(A,C); rs6656079(A,G); rs372561142(A,C); rs2297674(G,C); rs2228550(T,G); rs112748338(A,G); rs79699360(A,G); rs6657383(C,T); rs6681149(G,A); rs76019639(C,T); rs2228552(G,T); rs113045963(T,A); rs1815465(G,C); rs112942121(G,A); rs7536928(T,C); rs56232102(T,C); rs909000(C,T); rs10493049(A,G); rs16834691(C,T); rs72887344(C,T)
ccdsGene name	CCDS41297.1
cytoBand name	1p35.2
EntrezGene GeneID	1307
EntrezGene Description	collagen, type XVI, alpha 1
EntrezGene Type of gene	protein-coding
Annovar Function	COL16A1:NM_001856:exon46:c.C3016T:p.R1006W,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.6748
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	Q07092
dbNSFP Uniprot ID	COGA1_HUMAN
dbNSFP KGp1 AF	0.00412087912088
dbNSFP KGp1 Afr AF	0.0162601626016
dbNSFP KGp1 Amr AF	0.00276243093923
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0
dbSNP GMAF	0.004132
ESP Afr MAF	0.007466
ESP All MAF	0.002511
ESP Eur/Amr MAF	0.00012
ExAC AF	0.0008328

*OMIM Information*

OMIM Clinical Significance

Eyes:
Agenesis of macula;
Coloboma of macula

Inheritance:
Autosomal dominant

OMIM Title
*120326 COLLAGEN, TYPE XVI, ALPHA-1; COL16A1

OMIM Description

CLONING

Pan et al. (1992) cloned the gene for a new form of collagen with
features resembling those of members of the FACIT (fibril-associated
collagens with interrupted triple helices) group. Northern blot analyses
showed hybridization of the cDNA to a 5.5-kb mRNA in human fibroblasts
and keratinocytes.

By microarray analysis, Jun et al. (2001) demonstrated expression of the
COL16A1 gene in human donor corneas.

MAPPING

By in situ hybridization, Pan et al. (1992) localized the gene to
1p35-p34. They designated the collagen chain encoded by the cDNA the
alpha-1 chain of type XVI collagen. Yamaguchi et al. (1992) also cloned
and partially characterized the COL16A1 gene. Furthermore, they also
assigned the gene to chromosome 1 and regionalized it to 1p34-p13 by
examination of somatic cell hybrids containing spontaneous breaks or
translocations. Combined with the in situ hybridization data, the
findings suggested that the COL16A1 gene lies in the 1p34 band.

GENE FAMILY

The collagens fall into 2 major classes: the fibril-forming collagens
and the nonfibril-forming collagens. A long central triple-helical
domain, without gly-Xaa-Xaa interruptions, is the hallmark of the former
class; collagens type I, II, III, V, and XI, which form highly organized
fibrils in a quarter-staggered fashion, are members of this class. The
remaining collagens belong to the latter class with a common feature
being the presence of imperfections in the gly-Xaa-Xaa repeating
pattern. Within the latter class, collagens type IX, XII, and XIV form a
subgroup called the FACIT collagens (for 'fibril-associated collagens
with interrupted triple helices'). These collagens are associated with
type I or II collagen fibrils and play a role in interaction of these
fibrils with other matrix components (summary by Pan et al., 1992).

IQCC

dbSNP name	rs3903683(T,G); rs41302746(G,C)
ccdsGene name	CCDS355.1
cytoBand name	1p35.1
EntrezGene GeneID	55721
EntrezGene Description	IQ motif containing C
EntrezGene Type of gene	protein-coding
Annovar Function	IQCC:NM_018134:exon5:c.T626G:p.F209C,IQCC:NM_001160042:exon5:c.T866G:p.F289C,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.0
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	F5H7T8
dbNSFP KGp1 AF	0.173534798535
dbNSFP KGp1 Afr AF	0.308943089431
dbNSFP KGp1 Amr AF	0.151933701657
dbNSFP KGp1 Asn AF	0.222027972028
dbNSFP KGp1 Eur AF	0.0593667546174
dbSNP GMAF	0.1736
ESP Afr MAF	0.291648
ESP All MAF	0.141858
ESP Eur/Amr MAF	0.065116
ExAC AF	0.126

TSSK3

dbSNP name	rs61746387(C,T); rs35508255(A,G)
ccdsGene name	CCDS362.1
CosmicCodingMuts gene	TSSK3
cytoBand name	1p35.1
EntrezGene GeneID	81629
EntrezGene Description	testis-specific serine kinase 3
EntrezGene Type of gene	protein-coding
Annovar Function	TSSK3:NM_052841:exon2:c.C183T:p.I61I,
Annovar Mutation type	synonymous SNV
Annovar Region type	exonic
snpEff Effect	synonymous_coding
snpEff Functional Class	silent
snpEff Gene Biotype	protein_coding
snpEff Impact	low
dbSNP GMAF	0.01423
ESP Afr MAF	0.044258
ESP All MAF	0.014993
ESP Eur/Amr MAF	0.0
ExAC AF	0.003871

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

CARDIOVASCULAR:
[Heart];
Normal

SKIN, NAILS, HAIR:
[Skin];
Fragility with blistering (neonatal onset);
Palmoplantar keratosis with erythema and scale;
Hyperkeratotic plaques on trunk and limbs;
HISTOLOGY:;
Peripheral and cytoplasmic desmoplakin staining (immunohistochemistry)
ELECTRON MICROSCOPY:;
Acantholysis throughout all layers of the skin;
Focal detachment of desmosomes into the intercellular spaces;
Perinuclear condensation of the suprabasal keratin intermediate filament
network;
[Nails];
Nail dystrophy;
[Hair];
Alopecia;
Woolly hair;
Sparse eyelashes;
Sparse eyebrows

MOLECULAR BASIS:
Caused by mutations in the desmoplakin gene (DSP, 125647.0004)

OMIM Title
*607660 TESTIS-SPECIFIC SERINE/THREONINE KINASE 3; TSSK3
;;SERINE/THREONINE PROTEIN KINASE 22C; STK22C;;
STK22D, MOUSE, HOMOLOG OF; STK22D

OMIM Description

CLONING

Using degenerate primers corresponding to 2 highly conserved protein
kinase motifs, Visconti et al. (2001) cloned mouse Stk22d by PCR. Using
this sequence as query, they identified an EST containing the human
homolog of Stk22d, STK22C, and they obtained the full-length cDNA by
3-prime and 5-prime RACE of a testis cDNA library. The mouse and human
proteins contain 268 amino acids and share 100% amino acid homology.
Northern blot analysis of 8 human tissues detected transcripts of 1.0
and 1.35 kb only in testis. Transcription of Stk22d in mouse testis
began 20 to 24 days after birth. In adult mouse testis, expression was
detected in round and condensing spermatids, but not in meiotic
pachytene spermatocytes.

MAPPING

By FISH, Visconti et al. (2001) mapped the STK22C gene to chromosome
1p35-p34. They mapped its mouse homolog, Stk22d, to chromosome 4E1 in a
region showing homology of synteny to human 1p35-p34.

MACF1

dbSNP name	rs260972(C,T); rs72922966(A,G); rs260971(A,G); rs7546735(T,C); rs148019323(C,G); rs260970(G,A); rs59102092(A,C); rs260969(C,T); rs72922968(A,G); rs260968(A,G); rs72634502(C,T); rs77826036(T,C); rs260967(G,A); rs61780338(A,G); rs260966(T,C); rs147860177(T,G); rs260965(C,T); rs11205632(G,A); rs71642673(C,T); rs74714233(T,C); rs142004212(C,T); rs61066920(C,T); rs116057917(C,T); rs4660401(G,A); rs260964(T,C); rs59732233(G,A); rs12118033(G,A); rs139618353(C,T); rs56047998(A,G); rs260963(C,G); rs183910453(C,T); rs185470(G,A); rs687241(T,C); rs433065(G,A); rs72637903(G,A); rs112566467(C,T); rs11578150(T,C); rs11578277(T,A); rs56370363(G,A); rs113550032(G,A); rs80228263(T,C); rs260975(C,T); rs113603865(C,T); rs11581796(C,T); rs59244280(G,T); rs12117367(A,G); rs169010(T,C); rs141752713(C,T); rs365731(G,A); rs391138(G,A); rs434997(G,T); rs6667815(A,G); rs2282232(T,C); rs2282231(C,T); rs7535185(A,G); rs72660086(T,G); rs4660412(T,C); rs74069434(A,G); rs2036465(A,C); rs11580911(G,A); rs67637163(T,G); rs10788919(G,C); rs12126829(G,C); rs11205649(T,C); rs6691610(G,A); rs77756090(T,A); rs12124345(A,T); rs12407679(C,T); rs4660165(A,G); rs55693866(C,T); rs4660416(A,G); rs12137496(C,G); rs143527886(A,G); rs59274447(C,T); rs12128581(A,G); rs7550056(T,C); rs11205653(T,G); rs74069438(C,A); rs11580989(T,C); rs11205656(G,A); rs61386843(A,G); rs6684217(C,T); rs112205225(A,C); rs7555609(T,C); rs7543939(C,T); rs7520721(G,A); rs1967206(T,C); rs7544405(C,G); rs74069442(A,T); rs1472662(G,T); rs1021829(G,A); rs7550725(C,T); rs4660443(C,T); rs74393525(C,G); rs74702524(G,A); rs77927186(G,A); rs10788925(C,T); rs6600287(T,C); rs12075280(G,A); rs6600288(C,G); rs967529(A,G); rs967530(T,A); rs4660444(A,G); rs190170724(C,T); rs12354320(C,T); rs12354321(C,T); rs472310(C,T); rs472998(C,T); rs6661080(A,G); rs622988(C,G); rs79568645(A,G); rs67916282(T,A); rs2134472(T,G); rs111520806(T,A); rs77789426(G,A); rs12081736(A,G); rs533247(T,A); rs59983493(G,A); rs681019(C,G); rs11205684(A,G); rs4660475(A,G); rs590214(A,G); rs66848709(T,C); rs794636(C,T); rs12063189(C,G); rs6600289(C,T); rs646546(T,C); rs67452844(A,G); rs67062906(C,G); rs80343439(G,A); rs6679564(A,G); rs55734934(T,A); rs67408364(A,G); rs626520(C,A); rs11205695(A,C); rs624657(T,A); rs75778681(A,G); rs11205696(C,T); rs4660495(T,C); rs80297879(A,T); rs67758468(A,G); rs6600290(G,A); rs611412(C,G); rs10888682(A,T); rs10888683(A,T); rs660882(C,T); rs11205698(C,T); rs141612714(G,A); rs628523(A,G); rs74069446(T,C); rs60902398(A,G); rs526212(A,G); rs530768(G,A); rs143263635(C,G); rs12145367(G,C); rs656619(G,A); rs6703800(G,A); rs76718314(G,A); rs794642(G,A); rs140322812(G,A); rs12117785(G,T); rs66531516(G,A); rs114048950(G,A); rs16825863(T,G); rs661316(G,A); rs652370(T,C); rs71642677(C,T); rs12070815(C,T); rs583829(C,T); rs684581(C,T); rs502496(T,G); rs648697(G,A); rs651694(A,G); rs529887(C,T); rs17502518(C,T); rs6660622(A,G); rs10888688(A,G); rs604536(T,C); rs1537817(C,T); rs1126313(C,A); rs74069449(A,G); rs115229554(C,T); rs114260798(C,T); rs143090447(C,T); rs16825887(G,A); rs7554301(C,T); rs2455648(C,T); rs560372(G,A); rs561272(C,T); rs148849137(G,T); rs111533970(C,G); rs536193(C,T); rs595710(C,T); rs112672438(C,T); rs1537818(G,A); rs583572(C,T); rs112824904(C,T); rs688811(C,T); rs78373507(A,T); rs16825921(A,T); rs794641(C,G); rs636191(A,T); rs183731771(T,A); rs12087703(C,G); rs622621(G,A); rs145981577(A,C); rs530755(T,C); rs7538300(C,A); rs112765601(G,A); rs57214150(G,C); rs2992674(G,A); rs1290494(T,C); rs7542506(A,G); rs509301(G,C); rs12076577(G,T); rs509436(T,C); rs11205739(G,A); rs659286(T,C); rs2484762(G,T); rs520080(G,A); rs604993(A,G); rs3931300(A,G); rs74066703(G,A); rs16825939(G,A); rs16825942(G,A); rs142786949(C,T); rs6663999(G,C); rs12737392(G,A); rs148834186(C,T); rs1698831(A,C); rs496744(C,T); rs2484135(A,G); rs794638(A,T); rs72637904(C,T); rs72661925(T,A); rs115224511(A,C); rs74066704(G,C); rs78649283(A,T); rs12023553(C,A); rs112460686(G,A); rs16825953(A,G); rs591994(C,A); rs17491275(T,G); rs794637(C,T); rs59527424(G,T); rs113623989(G,A); rs16866216(A,G); rs6680962(G,C); rs74066706(C,T); rs6683629(G,A); rs72661927(A,G); rs669353(C,G); rs553560(A,G); rs4660543(A,G); rs651456(C,T); rs4660546(T,C); rs663978(A,G); rs975773(A,G); rs145142843(A,C); rs74066708(T,C); rs140615219(C,A); rs6692769(G,C); rs190455723(C,A); rs72637905(C,T); rs10493086(G,C); rs683583(C,T); rs138237429(C,T); rs142740781(T,C); rs112139327(A,C); rs582194(G,A); rs12057271(G,A); rs12069517(C,A); rs2036463(G,A); rs2036464(A,G); rs4660550(T,A); rs905381(T,G); rs12096683(A,T); rs626635(A,G); rs549393(T,C); rs12059756(T,G); rs667238(T,G); rs591199(C,T); rs495879(T,C); rs74066712(C,G); rs12089235(A,G); rs111701080(G,T); rs10788933(A,G); rs1112365(G,A); rs2490951(G,A); rs1932507(C,A); rs111496957(T,C); rs116735467(C,T); rs144021282(A,C); rs181424141(G,A); rs58716714(G,A); rs10888715(C,T); rs2254552(T,G); rs2254542(C,A); rs148780261(G,A); rs2254449(G,A); rs16837533(G,A); rs113056239(G,A); rs74066718(C,A); rs950805(A,C); rs1537819(G,A); rs12120111(G,A); rs3120279(C,T); rs3121892(G,A); rs148234053(G,A); rs2484759(A,G); rs72637906(G,A); rs71518423(A,G); rs67886352(G,A); rs2805584(G,A); rs2490947(T,C); rs60323161(T,C); rs151286488(A,G); rs66727439(C,T); rs7553009(C,T); rs1970232(C,T); rs111254532(T,C); rs16826000(G,T); rs2484758(G,C); rs11205823(T,A); rs1118139(A,G); rs2484756(A,G); rs16826009(A,G); rs58999516(G,A); rs10493087(C,G); rs2490948(T,C); rs12082877(C,T); rs2490949(A,T); rs12084111(C,T); rs12073705(G,A); rs11205828(C,T); rs16826012(T,C); rs66880209(G,A); rs55984302(G,A); rs74066722(C,G); rs4660208(A,G); rs79010504(G,C); rs2265408(C,T); rs7541085(T,C); rs7551353(G,A); rs2246257(G,A); rs2246160(A,G); rs77059509(A,C); rs74066723(A,G); rs140576655(G,A); rs1974240(G,T); rs74066724(T,G); rs1889830(A,G); rs77103344(G,A); rs79413694(T,C); rs2490950(G,A); rs4660214(T,C); rs6699928(T,G); rs11205839(G,A); rs148853384(A,G); rs16826022(G,C); rs74066725(T,G); rs74066726(T,C); rs115915034(G,A); rs4660603(C,G); rs145639560(C,T); rs74066727(G,A); rs945465(A,G); rs1537816(G,A); rs143620123(C,T); rs2252890(G,A); rs928680(A,G); rs12089264(T,C); rs3116387(T,G); rs2252549(A,T); rs2252538(G,A); rs2252410(T,G); rs1537815(A,G); rs1984142(G,C); rs150229974(A,G); rs2252049(A,G); rs12089090(T,C); rs74066729(C,T); rs3818806(G,A); rs2484751(C,A); rs74066730(A,G); rs41270799(G,A); rs74066731(A,G); rs2275188(G,A); rs74066732(A,G); rs3121896(C,T); rs146852195(G,T); rs59554900(T,C); rs373188019(G,A); rs2484750(C,T); rs1984143(G,A); rs143876874(G,A); rs2248212(T,C); rs16826036(G,C); rs146206218(C,T); rs16826038(G,A); rs2484749(A,G); rs6688708(C,G); rs16826046(A,G); rs116026083(G,C); rs1335747(T,G); rs111797516(A,G); rs61782157(C,T); rs7514695(G,T); rs2275187(G,A); rs41270803(A,G); rs2275186(C,T); rs74066735(C,T); rs9439001(A,G); rs12025847(G,A); rs57857317(G,A); rs112503435(G,A); rs80022002(T,G); rs115328404(A,T); rs61783376(T,C); rs945466(G,A); rs4660637(C,T); rs28643453(C,A); rs3121897(A,C); rs11205884(G,T); rs3120282(T,C); rs11205885(C,T); rs2484746(A,G); rs2490942(G,A); rs75505690(T,G); rs74718295(C,T); rs61783378(G,A); rs79963528(G,A); rs3116398(C,T); rs3121901(A,G); rs77086991(C,G); rs2377648(C,T); rs6692656(A,G); rs11205900(T,A); rs74066738(G,A); rs74066739(C,T); rs16826064(A,C); rs57633065(G,A); rs112943833(G,A); rs3116389(G,A); rs74066741(A,G); rs3116390(A,C); rs2889696(G,A); rs74066742(T,C); rs74066744(C,T); rs57016290(C,T); rs78389073(A,T); rs74066747(A,G); rs16826068(G,C); rs111745074(A,T); rs56221645(C,A); rs75120007(T,C); rs114768934(T,G); rs58746636(T,C); rs16826069(A,G); rs7547016(A,G); rs16826075(A,G); rs16826077(T,C); rs75770915(C,T); rs74066749(C,T); rs144022503(C,A); rs41270807(A,C); rs3121888(G,T); rs113149147(T,G); rs3121889(G,A); rs3116395(A,G); rs190681266(C,G); rs3121891(T,C); rs74066751(T,G); rs3116396(C,T); rs61783383(T,C); rs4660669(A,C); rs139416640(C,T); rs57037831(G,A); rs57657654(T,G); rs6704246(C,T); rs7528276(T,C); rs11807898(T,G); rs111623477(C,T); rs148552995(C,T); rs2490943(G,A); rs16826087(C,T); rs2490944(G,T); rs2761764(C,A); rs75075907(C,T); rs74066753(G,C); rs3754346(C,T); rs16826093(T,A); rs41270811(G,A); rs2805585(T,A); rs181803782(G,C); rs41270815(G,A); rs61779274(C,G); rs78707186(G,A); rs3118016(G,T); rs17264671(A,C); rs74066754(C,G); rs4660690(G,A); rs581422(C,T); rs593667(A,G); rs75510910(C,A); rs61779275(C,T); rs74066755(C,A); rs597311(T,G); rs597708(G,C); rs636083(T,C); rs16826103(C,T); rs636156(A,G); rs636158(T,A); rs1180373(G,A); rs146492646(G,C); rs613851(A,T); rs2256614(C,G); rs630519(T,C); rs74066763(G,T); rs143383087(T,C); rs112320204(T,A); rs583050(T,G); rs190801256(G,A); rs72661961(A,G); rs79105037(C,T); rs598415(T,C); rs613511(C,T); rs629093(A,G); rs61779277(G,A); rs61779278(A,G); rs596991(A,T); rs74066765(A,G); rs582883(T,C); rs2296172(A,G); rs12127668(C,A); rs59559317(G,A); rs61779279(C,T); rs74066767(C,T); rs2490945(T,C); rs2490946(G,A); rs80197726(T,C); rs61779282(C,G); rs7536582(G,C); rs621807(G,A); rs76111861(G,T); rs112334595(G,A); rs76256401(C,T); rs111905743(G,C); rs663834(A,G); rs663449(G,A); rs660293(T,C); rs79522721(T,G); rs592264(A,T); rs374973824(C,T); rs1180383(G,A); rs1184716(C,T); rs72661965(A,C); rs6668369(C,G); rs150902307(C,T); rs678672(A,T); rs74066769(G,A); rs666885(C,T); rs112451431(C,T); rs635943(T,C); rs149721483(A,G); rs112421123(T,G); rs61779284(G,A); rs6600291(G,A); rs74066771(C,T); rs3768299(G,A); rs12072631(A,G); rs12072715(A,G); rs6681763(C,T); rs584763(A,T); rs75731568(C,T); rs74066773(C,T); rs12096223(C,G); rs4660732(C,T); rs72928313(A,C); rs658255(T,G); rs60180523(C,A); rs12076554(A,G); rs7520599(G,A); rs61779285(C,T); rs2451672(T,G); rs74066776(C,T); rs3768300(C,T); rs3768301(C,T); rs80343368(C,G); rs74066778(T,C); rs616630(G,A); rs186663091(C,G); rs74066780(C,G); rs61073427(C,T); rs74066781(C,G); rs56278340(G,A); rs783823(A,G); rs3768302(T,G); rs653064(C,G); rs783826(T,C); rs115399293(A,G); rs72928327(T,A); rs1180376(A,G); rs61779300(G,A); rs2171979(T,A); rs74066796(C,T); rs1617212(A,G); rs1746844(T,C); rs1618798(A,G); rs1624820(C,A); rs663892(G,A); rs116243885(A,G); rs12063951(G,A); rs1180384(T,C); rs625384(C,T); rs60639051(T,C); rs116281812(A,G); rs2995513(T,C); rs645061(A,G); rs682571(G,A); rs683135(G,A); rs74066797(A,G); rs783817(C,A); rs6680153(C,T); rs599823(T,C); rs11206073(A,G); rs645234(G,T); rs783818(G,A); rs74066798(T,C); rs55975501(T,C); rs6663884(T,A); rs12061335(T,C); rs12075503(C,T); rs596705(T,C); rs12061378(T,C); rs1180372(A,G); rs2018212(T,C); rs653501(A,T); rs4660751(C,T); rs114364340(G,A); rs10489935(A,G); rs682351(A,G); rs11206102(A,C); rs587404(G,A); rs588326(A,G); rs116756012(T,C); rs78256423(A,T); rs617577(T,C); rs1775656(C,T); rs12069020(G,A); rs74972679(G,A); rs77637975(A,G); rs2296173(A,G); rs783837(C,G); rs3118014(G,A); rs16826152(G,A); rs668556(G,C); rs1180379(G,A); rs111998299(T,C); rs113356700(T,A); rs112898040(C,T); rs1180377(C,G); rs112635003(C,T); rs1746838(C,A); rs72930209(C,T); rs116060943(G,T); rs687848(A,G); rs688320(T,G); rs6671001(C,T); rs7540171(A,G); rs41270819(C,T); rs138078206(G,A); rs783841(A,T); rs61779306(G,A); rs599892(C,G); rs77563903(C,A); rs783840(G,T); rs41270821(T,C); rs658191(C,G); rs2296175(G,A); rs4660762(G,A); rs112836713(C,T); rs783820(G,A); rs112579533(A,G); rs188134768(A,C); rs1084760(T,C); rs7540050(C,A); rs7554206(T,C); rs6687066(C,T); rs813652(G,A); rs17511836(T,C); rs79420643(A,G); rs6698781(A,G); rs6698791(A,T); rs74910738(C,T); rs76030961(G,A); rs10888788(G,A); rs61779308(C,T); rs76803104(C,T); rs1623310(C,G); rs1775647(G,A); rs2995514(A,G); rs12057191(C,T); rs4617393(C,T); rs61779309(T,C); rs60295854(G,A); rs78035527(C,T); rs61779310(C,G); rs783827(A,C); rs783828(C,T); rs6665948(A,G); rs61779313(T,C); rs783829(G,A); rs722357(C,T); rs116784299(T,G); rs783830(C,T); rs2275767(C,T); rs796729(A,T); rs1626267(G,A); rs72930227(T,G); rs12138051(A,G); rs2995515(C,A); rs6691194(G,A); rs182511478(T,C); rs1775654(C,T); rs72930231(C,T); rs710915(G,A)
ccdsGene name	CCDS435.1
cytoBand name	1p34.3
EntrezGene GeneID	23499
EntrezGene Description	microtubule-actin crosslinking factor 1
EntrezGene Type of gene	protein-coding
Annovar Function	MACF1:NM_012090:exon14:c.G1532A:p.R511H,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.8625
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	F8W8Q1
ESP Afr MAF	0.0
ESP All MAF	7.7e-05
ESP Eur/Amr MAF	0.000116
ExAC AF	2.440e-05,8.132e-06

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Ears];
Deafness, sensorineural, prelingual, profound;
Nonprogressive deafness

MOLECULAR BASIS:
Caused by mutation in the hepatic growth factor gene (HGF, 142409.0001)

OMIM Title
*608271 MICROTUBULE-ACTIN CROSS-LINKING FACTOR 1; MACF1
;;MACROPHIN 1;;
TRABECULIN-ALPHA;;
ACTIN CROSS-LINKING FACTOR 7; ACF7;;
KIAA1251

OMIM Description

DESCRIPTION

ACF7 is a member of the spectraplakin family of cytoskeletal
cross-linking proteins that possess actin- and microtubule-binding
domains (Kodama et al., 2003).

CLONING

By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Nagase et al. (1999) cloned MACF1, which they designated
KIAA1251. The 3-prime UTR of the transcript contains Alu repeat
sequences, and the deduced protein contains 1,483 amino acids. RT-PCR
ELISA detected low expression of MACF1 in lung, ovary, and liver.

Sun et al. (1999) cloned several contiguous partial MACF1 cDNAs from a
prostate cDNA library and assembled the full-length sequence. The
deduced 5,373-amino acid MACF1 protein, which they designated
trabeculin-alpha, has a calculated molecular mass of 614 kD. MACF1 has
an N-terminal actin-binding domain, followed by a plectin (601282)-like
domain, 29 central spectrin (see 182860)-like repeats, and a C-terminal
region that contain 2 tandem Ca(2+)-binding EF-hand motifs, a GAR22
(GAS2L1; 602128)-like domain, and a serine-rich region. The C terminus
also has several putative tyrosine kinase motifs. MACF1 shares 88% amino
acid with its mouse homolog. Northern blot analysis detected MACF1
expression in all tissues examined, with highest expression in heart,
skeletal muscle, prostate, intestine, colon, and gonads. Lowest
expression was in brain, spleen, thymus, liver, placenta, and lung.
Immunofluorescence analysis of several cell lines detected MACF1
distributed in a filamentous network throughout the cytoplasm, with
exclusion from the nucleus.

By PCR of the HepG2 hepatoma cell line with degenerate primers based on
conserved C-terminal domains of FAK (600758) and CAKB (601212), followed
by screening a HepG2 cell line cDNA library, Okuda et al. (1999) cloned
MACF1, which they designated macrophin. The deduced 5,430-amino acid
protein has a calculated molecular mass of 620 kD. RT-PCR detected high
expression in heart, placenta, liver, kidney, and pancreas, moderate
expression in brain and lung, and weak expression in skeletal muscle. In
situ hybridization of pancreas showed mRNA mainly in acinar tissue.

By searching sequence databases using a chicken partial cDNA that was
differentially expressed during regeneration of the auditory epithelium
after noise trauma, followed by screening pituitary gland and heart cDNA
libraries, Gong et al. (2001) cloned a splice variant of MACF1. The
deduced protein, which they called MACF1-4, has a calculated molecular
mass of 670 kD, contains 8 N-terminal plectin repeats, and has no
actin-binding domain. The authors noted that 3 other splice variants
with different N termini had been identified for mouse Macf1. mRNA dot
blot analysis showed that MACF1 was expressed ubiquitously, with highest
expression in pituitary, adrenal, thyroid, salivary gland, mammary
gland, pancreas, heart, and skeletal muscle. mRNA dot blot analysis
using a riboprobe specific for the MACF1-4 variant showed highest
expression in heart, lung, pituitary gland, and placenta. PCR analysis
using MACF1-4-specific primers detected MACF1-4 in lung, heart,
pituitary, and placenta, but not in brain, kidney, liver, pancreas,
skeletal muscle, or HepG2 hepatoma cells.

GENE FUNCTION

By sedimentation binding assay, Sun et al. (1999) confirmed that the
N-terminal actin-binding domain of MACF1 coprecipitated with F-actin.
Cytochalasin D disruption of actin filaments also resulted in a marked
but incomplete disruption of MACF1 fine filament structures and the
appearance of punctate aggregates of MACF1. Mouse Macf1 mRNA levels
increased steadily during formation of fused myotubes during
differentiation in a mouse myoblasts cell line. Kodama et al. (2003)
showed that mouse Acf7 is an essential integrator of microtubule-actin
dynamics. In mouse endodermal cells, Acf7 bound along microtubules, but
concentrated at their distal ends and at cell borders when polarized. In
the absence of Acf7, microtubules still bound Eb1 (603108) and Clip170
(179838), but they no longer grew along polarized actin bundles, nor did
they pause and tether to actin-rich cortical sites. The consequences
were long, less stable microtubules with skewed cytoplasmic trajectories
and altered dynamic instability. In response to wounding, Acf7 null
cultures activated polarizing signals, but they failed to maintain them
and coordinate migration. Rescue of these defects required the actin-
and microtubule-binding domains of Acf7. Kodama et al. (2003) concluded
that spectraplakins are important for controlling microtubule dynamics
and reinforcing links between microtubules and polarized F-actin, so
that cellular polarization and coordinated cell movements can be
sustained.

Chen et al. (2006) found that siRNA knockdown of Macf1 inhibited Wnt
signaling (see WNT1; 164820) in a mouse embryonic carcinoma cell line.
Reporter gene assays indicated that Macf1 acted upstream of Gsk3b
(605004) in the Wnt signaling pathway. Macf1 interacted directly with
Axin (see AXIN1, 603816) and translocated with the Axin complex to the
cell membrane upon Wnt stimulation.

A resident population of adult stem cells (SCs) in hair follicles is
involved in hair growth and in epidermal reepithelialization during
wound healing. Wu et al. (2011) found that adult mouse hair follicle SCs
expressed high levels of Acf7 and that phosphorylation of Acf7 by
Gsk3-beta reduced the affinity of Acf7 for microtubules. Expression of a
constitutively active Gsk3-beta mutant in hair follicle SCs resulted in
elevated phosphorylation of Acf7 and altered microtubule structure
similar to that in Acf7-knockout cells. Conversely, inhibition of
Gsk3-beta increased microtubule binding by endogenous Acf7 in hair
follicle SCs. SC migration in a wound-healing assay was inhibited by
Acf7 knockout and by both over- and underactivation of Gsk3-beta. Wu et
al. (2011) concluded that cyclic phosphorylation of Acf7 by Gsk3-beta is
required for Acf7- and microtubule-based cell migration in hair follicle
SCs.

GENE STRUCTURE

Gong et al. (2001) determined that the MACF1 gene contains at least 102
exons and spans more than 270 kb.

MAPPING

By radiation hybrid analysis, Nagase et al. (1999) mapped the MACF1 gene
to chromosome 1. Okuda et al. (1999) mapped the MACF1 gene to chromosome
1p32-p31 by radiation hybrid analysis and genomic sequence analysis. By
FISH, Sun et al. (1999) mapped the MACF1 gene to chromosome 1p34.2-p33.
Gong et al. (2001) mapped the mouse Macf1 gene to a region of mouse
chromosome 4 that shows homology of synteny to human chromosome 1p32.

ANIMAL MODEL

Chen et al. (2006) found that Macf1 -/- mice died at the gastrulation
stage and displayed developmental retardation at embryonic day 7.5 with
defects in the formation of the primitive streak, node, and mesoderm.
The phenotype was similar to that of Wnt3 (165330)-null mice and Lrp5
(604506)/Lrp6 (603507) double-knockout mice.

NFYC-AS1

dbSNP name	rs552147(C,G); rs10789187(T,C); rs2780952(G,A); rs74718813(T,C); rs2744801(C,T); rs2744800(C,T); rs10789191(C,G)
cytoBand name	1p34.2
EntrezGene GeneID	100130557
EntrezGene Symbol	LOC100130557
snpEff Gene Name	NFYC
EntrezGene Description	uncharacterized LOC100130557
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	upstream
snpEff Functional Class	none
snpEff Gene Biotype	retained_intron
snpEff Impact	modifier
dbSNP GMAF	0.2599

SLFNL1

dbSNP name	rs41308248(A,G); rs372756325(C,T); rs61734928(C,T); rs145193833(C,T); rs147059742(C,T); rs6685430(G,T)
cytoBand name	1p34.2
EntrezGene GeneID	100507178
EntrezGene Symbol	SLFNL1-AS1
snpEff Gene Name	CTPS
EntrezGene Description	SLFNL1 antisense RNA 1
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.1143

HYI

dbSNP name	rs2251804(T,C); rs74069990(C,T); rs2251802(G,A); rs74069991(G,A)
ccdsGene name	CCDS488.2
cytoBand name	1p34.2
EntrezGene GeneID	81888
EntrezGene Description	hydroxypyruvate isomerase (putative)
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	processed_transcript
snpEff Impact	modifier
dbSNP GMAF	0.2668
ESP Afr MAF	0.184521
ESP All MAF	0.339228
ESP Eur/Amr MAF	0.418488
ExAC AF	0.322

LINC01144

dbSNP name	rs4451587(G,C)
cytoBand name	1p34.1
EntrezGene GeneID	400752
EntrezGene Symbol	LOC400752
snpEff Gene Name	ZSWIM5
EntrezGene Description	uncharacterized LOC400752
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	transcript
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.3168

LINC00853

dbSNP name	rs2245122(T,C)
cytoBand name	1p33
EntrezGene GeneID	100874253
snpEff Gene Name	PDZK1IP1
EntrezGene Description	long intergenic non-protein coding RNA 853
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	processed_transcript
snpEff Impact	modifier
dbSNP GMAF	0.3829

FOXD2-AS1

dbSNP name	rs77749789(C,T); rs3814005(T,C)
cytoBand name	1p33
EntrezGene GeneID	84793
snpEff Gene Name	FOXD2
EntrezGene Description	FOXD2 antisense RNA 1 (head to head)
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	upstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.009642

FOXD2

dbSNP name	rs2622917(G,A); rs2820966(G,A)
cytoBand name	1p33
EntrezGene GeneID	2306
EntrezGene Description	forkhead box D2
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR5
snpEff Effect	utr_5_prime
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.4587

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal recessive

GENITOURINARY:
[Kidneys];
Horseshoe kidney;
Ectopic kidney;
Absent kidney;
Dilated Bowman capsules;
Cystic tubular dilatation in the cortex and medulla;
[Ureters];
Double ureter

SKELETAL:
[Limbs];
Short, curved forearms;
Absence of the radii;
[Hands];
Medial flexion of the hands;
Absence of the thumbs

NEUROLOGIC:
[Central nervous system];
Hydrocephalus;
Ventriculomegaly;
Dilated ventricles

MISCELLANEOUS:
One family with 2 affected fetuses has been reported (as of August
2011)

OMIM Title
*602211 FORKHEAD, DROSOPHILA, HOMOLOG-LIKE 17; FKHL17
;;FORKHEAD-RELATED ACTIVATOR 9; FREAC9

OMIM Description

CLONING

Ernstsson et al. (1997) described the cloning of a nearly full-length
4,258-bp cDNA encoding the human forkhead gene FREAC9 (FKHL17). The
5-prime untranslated region is unusual since it is very long (2,127 bp)
and contains 15 upstream AUG codons. Hybridization to a panel consisting
of RNA derived from 50 different tissues showed that the FKHL17 gene is
transcribed exclusively in the kidney. The conceptual translation
product predicts a protein of 372 amino acids within an N-terminal
domain rich in acidic amino acids and with a high likelihood of forming
an amphipathic helix, a DNA binding forkhead domain, and a C-terminal
region that has a high probability of forming an amphipathic beta-sheet.
The amino acid sequence of the DNA binding forkhead motif of this
protein is identical to that of another forkhead protein, FREAC4
(601091), whereas 12 substitutions are present at the nucleotide level.
There are no similarities in regions outside of the DNA binding domains
of FREAC9 and FREAC4, and since the gene encoding the latter protein
maps to 5q12-q13, it is likely that evolutionary selection has acted to
maintain identical DNA binding domains between these 2 kidney-expressed
transcription factors.

MAPPING

By a combination of fluorescence in situ hybridization and somatic cell
hybrid analyses, Ernstsson et al. (1997) localized the FKHL17 gene to
chromosome 1p34-p32. Ernstsson et al. (1997) tabulated the chromosomal
localization of 15 human forkhead genes in their Table 1.

KTI12

dbSNP name	rs2809918(C,A); rs2809917(C,T); rs2783175(A,T); rs114190370(C,A)
ccdsGene name	CCDS561.1
cytoBand name	1p32.3
EntrezGene GeneID	112970
snpEff Gene Name	TXNDC12
EntrezGene Description	KTI12 homolog, chromatin associated (S. cerevisiae)
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	processed_transcript
snpEff Impact	modifier
dbSNP GMAF	0.02847

CPT2

dbSNP name	rs3766760(G,T); rs2062015(C,G); rs2046138(G,A); rs12754957(T,C); rs78117157(C,T); rs3766759(T,G); rs139929212(A,T); rs150278375(C,G); rs59327204(G,A); rs148984426(G,A); rs187203767(T,G); rs142503511(T,C); rs141137174(T,G); rs11206125(A,C); rs11581518(A,G); rs192071234(G,A); rs7539949(G,A); rs78717670(C,T); rs1072706(T,C); rs187187529(T,C); rs140577958(G,A); rs191317017(T,C); rs184420650(T,C); rs11578832(G,A); rs143421390(C,T); rs370493(G,A); rs12737375(T,C); rs145237292(A,G); rs141553491(G,T); rs1799821(G,A); rs142600166(G,A); rs6692897(A,G); rs188460484(C,T); rs737464(A,G); rs181453495(C,A); rs141146189(G,A); rs1799822(A,G)
ccdsGene name	CCDS575.1
cytoBand name	1p32.3
EntrezGene GeneID	1376
EntrezGene Description	carnitine palmitoyltransferase 2
EntrezGene Type of gene	protein-coding
Annovar Function	CPT2:NM_000098:exon4:c.A877G:p.S293G,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.6506
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	P23786
dbNSFP Uniprot ID	CPT2_HUMAN
ESP Afr MAF	0.0
ESP All MAF	0.000154
ESP Eur/Amr MAF	0.000233
ExAC AF	8.945e-05

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal recessive

CARDIOVASCULAR:
[Heart];
Cardiomegaly;
Dilated cardiomyopathy

RESPIRATORY:
Respiratory arrest

ABDOMEN:
[Liver];
Hepatomegaly;
Macrovesicular steatosis;
[Gastrointestinal];
Vomiting

NEUROLOGIC:
[Central nervous system];
Lethargy;
Seizures

METABOLIC FEATURES:
Hypoketotic hypoglycemia

LABORATORY ABNORMALITIES:
Decreased carnitine palmitoyltransferase II (CPT2) activity;
Decreased levels of CPT2 protein;
Decreased palmitate oxidation;
Increased liver function tests;
Hyperammonemia;
Increased creatine kinase;
Reduced total and free carnitine in plasma and tissue;
Increased long-chain acylcarnitine

MISCELLANEOUS:
Onset in infancy (3 months on);
Precipitated by febrile illness and fasting;
See also lethal neonatal (608836) and adult forms (255110)

MOLECULAR BASIS:
Caused by mutations in the carnitine palmitoyltransferase II gene
(CPT2, 600650.0001)

OMIM Title
*600650 CARNITINE PALMITOYLTRANSFERASE II; CPT2
;;CPT II

OMIM Description

DESCRIPTION

The CPT2 gene encodes carnitine palmitoyltransferase II, an enzyme that
participates in fatty acid oxidation. The carnitine palmitoyltransferase
(CPT; EC 2.3.1.21) enzyme system, in conjunction with acyl-CoA
synthetase and carnitine/acylcarnitine translocase (613698), provides
the mechanism whereby long-chain fatty acids are transferred from the
cytosol to the mitochondrial matrix to undergo beta-oxidation. The CPT I
isozymes (see CPT1A; 600528 and CPT1B; 601987) are located in the
mitochondrial outer membrane and are detergent-labile, whereas CPT II is
located in the inner mitochondrial membrane and is detergent-stable
(Bieber, 1988).

CLONING

By screening a human liver cDNA library, Finocchiaro et al. (1991)
cloned and sequenced a cDNA encoding human carnitine
palmitoyltransferase II. The deduced 658-amino acid protein contains a
25-residue NH2-terminal leader peptide. The amino acid sequence shows
82.2% homology with the rat CTP II protein.

Montermini et al. (1994) identified regulatory elements in the promoter
of the CPT2 gene.

GENE STRUCTURE

Verderio et al. (1995) determined that the CPT2 gene contains 5 exons
spanning approximately 20 kb of DNA.

MAPPING

By human-hamster somatic cell hybridization, Finocchiaro et al. (1991)
assigned the CPT2 gene (which they referred to as CPT1) to chromosome
1pter-q12. By fluorescence in situ hybridization, Minoletti et al.
(1992) refined the assignment of the CPT2 gene to 1p13-p11. However,
also using fluorescence in situ hybridization, Gellera et al. (1994)
concluded that the CPT2 gene is located in band 1p32 and that the
previously used probe that mapped the gene to 1p13-p11 'must be
considered an as yet anonymous probe.' It is now clear that the gene
mapped to chromosome 1p32 was CPT2.

GENE FUNCTION

Britton et al. (1995) distinguished CPT I and CPT II, and reported that
major control over the fatty acid oxidation process is exerted at the
level of CPT I by the unique inhibition of this enzyme by malonyl-CoA.

Slama et al. (1996) carried out complementation experiments between cell
lines derived from patients with CPT I deficiency (255120) or infantile
CPT II deficiency (600649) by measuring restoration of tritium release
from palmitate. As expected, no complementation was observed in
heteropolykaryons resulting from fusion of CPT I-deficient cells or of
CPT II-deficient cells. Conversely, complementation was observed in
fusions of CPT I- and CPT II-deficient cells. These data suggested that
the defects in CPT I deficiency and infantile CPT II deficiency are
determined by mutations in distinct genes. Palmitate oxidation by
control or CPT I-deficient cell lines decreased when these cell lines
were cocultured with infantile CPT II-deficient cell lines. This effect,
not observed in a coculture with an adult CPT II-deficient cell line,
was suppressed by a high carnitine concentration.

NOMENCLATURE

Finocchiaro et al. (1991), Minoletti et al. (1992), and Gellera et al.
(1994) all referred to the CPT gene on chromosome 1 as CPT1; it is
referred to here as CPT2 following the elucidation by Britton et al.
(1995). CPT1 (600528) maps to chromosome 11.

MOLECULAR GENETICS

- Carnitine Palmitoyltransferase II Deficiency

In a patient with infantile carnitine palmitoyltransferase II deficiency
(600649) with hypoketotic hypoglycemia and cardiomyopathy, Taroni et al.
(1992) identified a homozygous mutation in the CPT2 gene (600650.0001).
The patient was also homozygous for a mutant CPT2 allele (termed the
'ICV' allele) that carried 2 other rare polymorphisms. In a patient with
infantile CPT II deficiency reported by Demaugre et al. (1991),
Bonnefont et al. (1996) identified a homozygous mutation in the CPT2
gene (600650.0005).

In a Dutch patient with adult-onset CPT II deficiency (255110), Taroni
et al. (1993) identified compound heterozygosity for 2 mutations in the
CPT2 gene (600650.0001; 600650.0002).

Elpeleg et al. (2001) reported 2 Ashkenazi Jewish sibs with the
antenatal, or lethal neonatal, form of CPT II deficiency (608836) who
were homozygous for an allele carrying 2 mutations in exon 4 of the CPT2
gene (600650.0009).

Isackson et al. (2008) identified compound heterozygous or homozygous
mutations in the CPT2 gene in 3 patients with lethal neonatal CPT II
deficiency (see, e.g., 600650.0013) and in 2 patients with infantile CPT
II deficiency. Three of the mutations were novel (see, e.g.,
600650.0017).

- Infection-Induced Acute Encephalopathy-4

Chen et al. (2005) found that a Japanese girl with fatal
infection-induced acute encephalopathy-4 (IIAE4; 614212) was
heterozygous for a thermolabile allele in the CPT2 gene (600650.0018).
She had significantly increased serum acylcarnitine levels during
febrile convulsions. Her 2 unaffected brothers, who were heterozygous
for the allele, and their father, who was homozygous for the allele, had
slightly increased serum acylcarnitine compared to normal values in the
nonfebrile state. The mother, who was heterozygous only for the 368I,
had normal acylcarnitine levels in the nonfebrile state.

GENOTYPE/PHENOTYPE CORRELATIONS

In a study of 19 patients with CPT II deficiency, 13 with adult onset
and 6 with infantile onset, Thuillier et al. (2003) found that all
patients with the infantile form had mutations in exon 4 or 5 of the
CPT2 gene. Twelve of the adult patients carried the S113L (600650.0002)
mutation. Although there was an overlap in residual CPT II activity
between the 2 groups (ranging from 4 to 12%), there was a significant
decrease in palmitate oxidation in the infantile group (less than 10%)
compared to the adult group (45 to 70%). Thuillier et al. (2003)
concluded that both the type and location of CPT2 mutations and at least
1 additional, unidentified genetic factor modulate the long-chain fatty
acid flux and therefore the severity of the disease.

Orngreen et al. (2005) identified 2 unrelated patients with mild
features of late-onset CPT II deficiency who each carried a single
mutation in the CPT2 gene (600650.0015 and 600650.0016). The findings
indicated that some heterozygous CPT2 mutation carriers may be
symptomatic.

SLC25A3P1

dbSNP name	rs1299818(G,C); rs1288598(T,G)
cytoBand name	1p32.3
EntrezGene GeneID	163742
snpEff Gene Name	RP4-796B4.1
EntrezGene Description	solute carrier family 25 (mitochondrial carrier
EntrezGene Type of gene	pseudo
Annovar Region type	ncRNA_exonic
snpEff Effect	transcript
snpEff Functional Class	none
snpEff Gene Biotype	processed_pseudogene
snpEff Impact	modifier
dbSNP GMAF	0.326

MIR4781

dbSNP name	rs74085143(G,A)
cytoBand name	1p32.3
EntrezGene GeneID	100616315
snpEff Gene Name	TCEANC2
EntrezGene Description	microRNA 4781
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	processed_transcript
snpEff Impact	modifier
dbSNP GMAF	0.09963
ExAC AF	0.019

LOC100507634

dbSNP name	rs10788995(A,T)
cytoBand name	1p32.3
EntrezGene GeneID	100507634
snpEff Gene Name	USP24
EntrezGene Description	uncharacterized LOC100507634
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	upstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.281

MIR4422

dbSNP name	rs17111728(T,C)
cytoBand name	1p32.3
EntrezGene GeneID	100616272
snpEff Gene Name	GYG1P3
EntrezGene Description	microRNA 4422
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	processed_pseudogene
snpEff Impact	modifier
dbSNP GMAF	0.07713
ExAC AF	0.03

C8A

dbSNP name	rs72670316(G,A); rs1342434(T,C); rs1342433(G,A); rs857029(A,G); rs182518760(G,A); rs145666509(C,A); rs148823214(A,G); rs622300(G,A); rs857028(T,G); rs634144(C,T); rs636879(C,T); rs662377(A,G); rs77725725(A,G); rs663352(T,A); rs664142(A,G); rs17114468(G,A); rs11802385(G,A); rs113719307(T,A); rs77187136(T,C); rs621819(C,T); rs622299(C,T); rs150491061(G,T); rs635922(T,C); rs77696206(G,A); rs72670317(C,A); rs6669054(T,G); rs668822(G,T); rs1891420(A,G); rs34047108(A,G); rs601662(A,G); rs603154(A,G); rs12406202(G,T); rs146392023(T,C); rs2269121(T,C); rs618238(G,C); rs1581942(C,T); rs618707(G,A); rs12401558(C,T); rs72670319(G,A); rs57210737(G,T); rs694090(G,T); rs2269119(G,C); rs1887977(G,A); rs706473(A,G); rs114890786(A,G); rs75068333(A,G); rs927214(G,T); rs1885002(A,G); rs652785(C,A); rs2269118(G,A); rs607221(C,T); rs594105(T,G); rs645846(A,G); rs706474(T,C); rs706475(T,A); rs2269115(C,T); rs17114506(T,C); rs2300955(G,A); rs17114511(A,G); rs2300954(T,C); rs6681119(A,T); rs1754519(A,G); rs11804514(G,T); rs77604905(A,C); rs856842(A,T); rs706476(A,C); rs6588656(C,T); rs6694643(A,T); rs6697228(T,C); rs10489624(T,C); rs80226443(T,G); rs58983677(C,T); rs181653329(A,C); rs35562962(A,C); rs72670327(C,T); rs114404344(T,G); rs658461(A,G); rs629799(A,G); rs28472455(A,G); rs2269114(T,C); rs6668097(C,T); rs6683663(A,G); rs6686359(T,C); rs6696110(T,G); rs6696924(T,G); rs6699859(T,C); rs6670243(C,T); rs1411012(A,T); rs11206932(T,A); rs3768215(C,T); rs6700128(G,C); rs2145404(G,T); rs1360151(C,T); rs679350(G,A); rs1999133(G,A); rs1329450(T,C); rs78083553(G,A); rs6661831(G,A); rs6662705(G,A); rs585061(T,C); rs11206933(A,G); rs620709(G,A); rs608567(A,G); rs1360149(C,G); rs2284952(G,T); rs2284951(T,A); rs592451(A,G); rs12116668(T,C); rs619545(C,T); rs7520004(G,A); rs7520006(G,A); rs1411009(T,C); rs607422(C,T); rs17114555(G,A); rs624298(A,G); rs61350393(G,T); rs682479(C,A); rs74893427(A,C); rs638919(T,C); rs116296609(T,C); rs635833(C,T); rs1620075(G,A); rs623077(T,C); rs11206934(T,C); rs145849377(G,A); rs607268(T,C); rs56143927(C,T); rs2284950(G,A); rs186013951(G,A); rs139810278(C,A); rs115806842(C,T); rs72670338(C,T)
ccdsGene name	CCDS606.1
cytoBand name	1p32.2
EntrezGene GeneID	731
EntrezGene Description	complement component 8, alpha polypeptide
EntrezGene Type of gene	protein-coding
Annovar Function	C8A:NM_000562:exon10:c.G1454A:p.R485H,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.5732
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	P07357
dbNSFP Uniprot ID	CO8A_HUMAN
dbSNP GMAF	0.08815
ExAC AF	0.077,1.830e-03,8.132e-06

*OMIM Information*

OMIM Clinical Significance

Immunology:
Partial C4 deficiency;
Systemic lupus erythematosus

Inheritance:
Autosomal dominant

OMIM Title
*120950 COMPLEMENT COMPONENT 8, ALPHA SUBUNIT; C8A
;;C8 ALPHA

OMIM Description

DESCRIPTION

The eighth component of complement (C8) belongs to the late-acting
complement proteins (C5-C9) forming the membrane attack complex. C8 is a
serum protein that consists of 3 nonidentical subunits arranged
asymmetrically as a disulfide-linked alpha (C8A)-gamma (C8G; 120930)
dimer and a noncovalently associated beta chain (C8B; 120960). Each
component is encoded by a different gene (Kolb and Muller-Eberhard,
1976; Ng et al., 1987).

BIOCHEMICAL FEATURES

By separating the alpha-gamma dimer of C8 from the beta chain and then
subjecting the alpha-beta dimer to further treatment, Brickner and
Sodetz (1985) purified the alpha and gamma chains. When mixed, purified
alpha and gamma exhibited high affinity for each other, and purified
gamma also had affinity for C8-prime, which is composed of the alpha and
beta chains only. Brickner and Sodetz (1985) concluded that alpha
possesses a specific site for interaction with gamma and that the site
remains accessible in the isolated alpha subunit and when alpha is
associated with beta. They found that gamma associated specifically with
membrane-bound C5b-8-prime and C5b-(8-prime)9 complexes. Brickner and
Sodetz (1985) concluded that the gamma interaction site on alpha remains
accessible in C5b-8-prime and is not shielded by C9 within
C5b-(8-prime)9, and that the gamma subunit of C8 is located on the
surface of membrane-bound C5b-8 and C5b-9.

Hadders et al. (2007) determined the crystal structure of the MACPF
(membrane attack complex perforin) domain of the complement component
C8-alpha at 2.5-angstrom resolution and showed that it is structurally
homologous to the bacterial, pore-forming, cholesterol-dependent
cytolysins. The structure displayed 2 regions that in the bacterial
cytolysins refold into transmembrane beta hairpins, forming the lining
of a barrel pore. Local hydrophobicity explained why C8-alpha is the
first complement protein to insert into the membrane. The size of the
MACPF domain is consistent with known C9 pore sizes. Hadders et al.
(2007) concluded that their data implied that these mammalian and
bacterial cytolytic proteins share a common mechanism of membrane
insertion.

Rosado et al. (2007) determined the crystal structure of a bacterial
MACPF protein, Plu-MACPF from Photorhabdus luminescens, to 2.0-angstrom
resolution. The MACPF domain revealed structural similarity with
pore-forming cholesterol-dependent cytolysins from gram-positive
bacteria. Rosado et al. (2007) suggested that lytic MACPF proteins may
use a cholesterol-dependent cytolysin-like mechanism to form pores and
disrupt cell membranes.

GENE STRUCTURE

Michelotti et al. (1995) isolated overlapping genomic clones and used
them to decipher the organization of the human C8A gene. The gene
contains at least 11 exons and spans approximately 70 kb of DNA. C8A
genomic organization was found to be remarkably similar to that of C6,
C8B, and C9.

MAPPING

Rogde et al. (1984) found that the polymorphism detected by anti-C8 was
determined by a locus linked to PGM1 on 1p (maximal lod score, sexes
combined, of 8.0 at theta = 0.10). They interpreted their evidence as
suggesting that this polymorphism is in the alpha-gamma subunit. By
2-dimensional electrophoresis, Rogde et al. (1985) showed that the C8
polymorphism resides in the structural gene for the alpha chain.

Using separation by isoelectric focusing followed by immunoblotting,
Rogde et al. (1985, 1986) concluded that C8A and C8B are closely linked
to each other (lod = 3.01, theta 0.0) and to PGM1 (171900): C8A, lod =
16.5 at theta 0.09; C8B, lod = 3.54 at theta 0.11, sexes combined. Both
C8 loci are linked to Rh (maximum lod = 3.56 at theta 0.23 in males and
0.36 at theta 0.37 in females).

Rittner et al. (1986) showed that the C8A gene and PGM1 were linked with
male theta of 0.18 and female theta of 0.26. The sum of the lods for 9
families was 1.822. The genetic distances between the two C8 loci and
PGM1 appeared to be identical in males and females (Rogde et al., 1986).
As noted, a female/male ratio of 1.6 was observed between the two C8
loci and Rh. No evidence of linkage of the C8 loci to Fy was found.

Using cDNA clones for the C8-alpha and C8-beta genes for nonradioactive
in situ hybridization, Theriault et al. (1991, 1992) mapped the 2 genes
to 1p32. For both subunits the results were confirmed by hybridization
to metaphase chromosomes derived from a person with the balanced
reciprocal translocation t(1;5)(p32;q35), the hybridization signal being
observed on the derivative chromosome 5. Using BamHI RFLPs of the C8A
and C8B genes, Rogde et al. (1992) obtained a peak lod score of 4.52 at
recombination fraction of 0.0 between C8A and C8B. Combined with data
from a previous study, a maximum lod score of 22.02 at recombination
fraction 0.11, with no sex difference, was compiled for the C8-PGM1
linkage. No evidence of allelic association between the C8A and C8B
BamHI RFLPs was found.

Although the C8A and C8B loci were previously reported to be less than
2.5-kb apart, Michelotti et al. (1995) obtained results using
exon-specific probes, indicating that the loci are not as closely linked
as initially believed.

MOLECULAR GENETICS

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

In 2 unrelated Japanese patients with C8 alpha/gamma deficiency
(613790), Kojima et al. (1998) screened all 11 exons of the C8A gene and
all 7 exons of the C8G gene and their boundaries and identified
homozygous or compound heterozygous mutations in the C8A gene
(120950.0002-120950.0003). No mutation was found in the C8G gene.

ANIMAL MODEL

Komatsu et al. (1985) and Komatsu et al. (1990) described hereditary
C8-alpha-gamma deficiency in the rabbit where it was associated with
dwarfism, small thymus, small litter size, and low survival rate.
Komatsu et al. (1990) showed that the C8 deficiency was not linked to
the dw-2 locus which causes dwarfism in rabbits. Whether the dwarfism
was due to a separate locus closely linked to the C8 locus or was a
pleiotropic effect of the C8 locus was unclear.

HISTORY

Merritt et al. (1976) concluded, through family linkage studies, that a
gene for C8 is in the HLA region. Other studies failed to confirm
linkage with HLA (e.g., Giraldo et al., 1977).

Alper et al. (1983) demonstrated a second C8 polymorphism by isoelectric
focusing of serum in polyacrylamide gel and development of specific
patterns of hemolysis in an overlay gel containing C8 beta-chain
deficiency.

Nakamura et al. (1986) reported on C81 polymorphism in the Japanese.

C8B

dbSNP name	rs605648(T,C); rs653804(C,G); rs2281598(C,G); rs642535(G,C); rs642120(T,G); rs603804(G,A); rs641714(G,C); rs591730(A,G); rs2025006(C,T); rs638423(C,T); rs684844(A,G); rs684782(C,T); rs684304(T,C); rs683824(G,A); rs612563(G,C); rs668451(C,T); rs652962(G,T); rs652553(T,C); rs581992(T,A); rs676480(A,C); rs17301153(C,T); rs594661(T,C); rs139787516(C,T); rs684216(C,G); rs116064367(A,C); rs669358(C,T); rs142113157(G,T); rs622904(A,T); rs725330(C,T); rs6669836(T,C); rs628745(T,C); rs72670358(A,G); rs626457(C,T); rs114102078(C,T); rs111927445(T,A); rs150601390(G,A); rs3768214(G,C); rs189023811(C,T); rs598772(C,T); rs11807035(T,C); rs856840(T,C); rs656598(A,C); rs72670362(C,A); rs141136423(G,A); rs2269113(C,T); rs78766017(T,C); rs597181(G,T); rs72670363(T,C); rs145392333(A,G); rs149212188(A,T); rs582317(G,A); rs12085435(G,A); rs661449(A,G); rs12136853(G,T); rs659710(A,G); rs658285(G,A); rs116022276(C,T); rs78165833(G,A); rs646606(A,G); rs706482(C,A); rs679477(T,C); rs74867817(G,A); rs1960384(C,A); rs114930135(C,T); rs7553563(G,A); rs78415143(G,A); rs649069(C,A); rs614020(G,A); rs115511830(G,A); rs647571(T,C); rs145514947(G,T); rs75015103(A,G); rs138138954(C,T); rs706483(T,C); rs142321498(C,A); rs41452950(A,G); rs585762(A,G); rs620092(C,T); rs664979(A,G); rs114173524(A,G); rs617283(A,G); rs7525070(C,T); rs56023405(A,C); rs7541538(T,C); rs1013579(C,T); rs12067507(C,T); rs114982349(G,C); rs7542230(T,C); rs605632(C,T); rs604842(C,G); rs146494180(T,G); rs586902(T,C); rs683916(A,T); rs112036408(G,A); rs668555(T,C); rs12092641(T,C); rs72670376(G,A); rs7512725(T,C); rs637253(A,G); rs599857(T,C); rs706484(T,C); rs737097(G,A); rs927212(T,C); rs927211(G,A); rs927210(A,G); rs150683548(A,T); rs2236217(C,A); rs2236216(C,T); rs146092968(T,C); rs61767007(G,A); rs78501968(G,A); rs75000477(A,G)
ccdsGene name	CCDS30730.1
cytoBand name	1p32.2
EntrezGene GeneID	732
EntrezGene Description	complement component 8, beta polypeptide
EntrezGene Type of gene	protein-coding
Annovar Function	C8B:NM_001278543:exon8:c.C856T:p.R286C,C8B:NM_001278544:exon8:c.C826T:p.R276C,C8B:NM_000066:exon7:c.C1012T:p.R338C,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.6249
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	F5H7G1
dbNSFP KGp1 AF	0.00228937728938
dbNSFP KGp1 Afr AF	0.00813008130081
dbNSFP KGp1 Amr AF	0.0
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.00131926121372
dbSNP GMAF	0.002296
ESP Afr MAF	0.000227
ESP All MAF	7.7e-05
ESP Eur/Amr MAF	0.0
ExAC AF	0.0001626

*OMIM Information*

OMIM Clinical Significance

Immunology:
Partial C4 deficiency;
Systemic lupus erythematosus

Inheritance:
Autosomal dominant

OMIM Title
*120960 COMPLEMENT COMPONENT 8, BETA SUBUNIT; C8B
;;COMPLEMENT COMPONENT C8B;;
C8 BETA

OMIM Description

DESCRIPTION

The eighth component of complement (C8) belongs to the late-acting
complement proteins (C5-C9) forming the membrane attack complex. C8 is a
serum protein that consists of 3 nonidentical subunits arranged
asymmetrically as a disulfide-linked alpha-gamma dimer (C8A, 120950;
C8G, 120930) and a noncovalently associated beta chain (C8B). Each
component is encoded by a different gene (Ng et al., 1987; Kaufmann et
al., 1993).

GENE STRUCTURE

Herrmann et al. (1989) estimated the size of the C8B gene to be 32 to 36
kb.

By using PCR primers located in the adjacent intron sequences of C8B,
Kaufmann et al. (1993) could amplify all 12 exons of the C8B gene from
genomic DNA. These analyses and the insert sizes of the genomic lambda
clones indicated that the C8B gene has a total size of approximately 40
kb.

MAPPING

The C8A and C8B genes are closely linked on chromosome 1p (Rogde et al.,
1986).

Bahary et al. (1991) mapped the murine homolog of C8B to chromosome 4.

MOLECULAR GENETICS

By direct sequence analysis of all exon-specific PCR products from
normal and C8B-deficient persons, Kaufmann et al. (1993) found a single
C-T change in exon 9 leading to a stop codon (R428X; 120960.0001). An
allele-specific PCR system was designed to detect the normal and the
deficiency allele simultaneously. Using this approach as well as PCR
typing of the TaqI polymorphism located in intron 11, 5 families with 7
C8B-deficient members were investigated. The mutant allele was observed
in all families investigated and could therefore be regarded as a major
cause of C8B deficiency in Caucasians. In 2 C8B-deficient patients, only
1 chromosome carried the C-T change; the molecular nature of the other
allele had not been determined.

In a study of 34 unrelated families with C8B deficiency from the U.S.
and the former U.S.S.R., Saucedo et al. (1995) found that 59 (86%) of 69
null alleles were due to the C-to-T transition in exon 9. An additional
6 null alleles were caused by C-to-T transitions in exons 3 (120960.0003
and 120960.0004) and 6 (120960.0002). Two null alleles were caused by
cytosine deletions in exons 3 (120960.0005) and 5 (120960.0006). Of the
null alleles, 97% were C-to-T transitions in which an arg (64 alleles)
or gln (1 allele) was replaced by a stop codon.

- C8B Mutation Nomenclature

Using current recommendations for mutation nomenclature, Arnold et al.
(2009) numbered nucleotides of the C8B gene starting at the A of the ATG
translational start site of the coding reference sequence GENBANK
NM_000066. They noted that, traditionally, C8B nucleotides had been
numbered starting at the 5-prime end of cDNA clone GENBANK M16973. In
their Table 2, Arnold et al. (2009) provided a comparison of the
recommended mutation nomenclature used by them with the traditional
mutation nomenclature used by others, including Kaufmann et al. (1993),
Saucedo et al. (1995), and Rao et al. (2004), along with the
corresponding protein changes.

TACSTD2

dbSNP name	rs7333(C,T); rs9583(T,C); rs3551(A,G); rs41311174(C,T)
cytoBand name	1p32.1
EntrezGene GeneID	4070
EntrezGene Description	tumor-associated calcium signal transducer 2
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	utr_3_prime
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.2241

*OMIM Information*

OMIM Clinical Significance

GI:
Giant hypertrophic gastritis;
Enlarged gastric mucosal folds

Lab:
Gastric glandular proliferation with nuclear polarity preservation
and cystic dilatation of gland base;
Hypochlorhydria;
Hypoproteinemia;
recessive

OMIM Title
*137290 TUMOR-ASSOCIATED CALCIUM SIGNAL TRANSDUCER 2; TACSTD2
;;MEMBRANE COMPONENT, CHROMOSOME 1, SURFACE MARKER 1; M1S1;;
GASTROINTESTINAL TUMOR-ASSOCIATED ANTIGEN 1, 40-KD GLYCOPROTEIN; GA733-1;;
GA733

OMIM Description

DESCRIPTION

The monoclonal antibody GA733 was derived from the immunization of mice
with a human stomach adenocarcinoma cell line. It has specificity to
carcinomas of other origins, such as the cervix, bladder, and lung.

CLONING

Linnenbach et al. (1989) purified the antigen from a human colorectal
carcinoma cell line and determined its partial amino acid sequence. By
using a synthetic oligonucleotide probe, they isolated 2 recombinants
from a total human genomic library. They demonstrated the existence of a
family of GA733 genes. One of the isolates had no introns; it was
transcribed in pancreatic carcinoma cell lines and in placenta. The
GA733 proteins were found to contain sequences homologous to a repeat
unit occurring 10 times in thyroglobulin (188450) and once in the
HLA-DR-associated invariant chain (142790).

Fornaro et al. (1995) cloned a cDNA encoding the GA733-1 from an ovarian
carcinoma cDNA expression library. The cDNA encodes a predicted
323-amino acid polypeptide of 35,709 Da that is 48% similar to the
GA733-2 polypeptide (EPCAM; 185535). The regions of homology cluster in
2 extracytoplasmic domains and in the putative transmembrane/cytoplasmic
region. A potential cytoplasmic phosphorylation site is also conserved.
The gene is also designated M1S1 for membrane component, chromosome 1,
surface marker 1.

GENE STRUCTURE

Linnenbach et al. (1993) stated that the single-exon gene encoding
GA733-1 contains a long ORF of 323 amino acids encoding a predicted
35.7-kD protein with 4 potential N-linked glycosylation sites. The
authors found that the amino acid sequences of GA733-1 and of the
314-residue GA733-2 predicted protein are 49% identical. From additional
sequence studies of the 9-exon GA733-1 gene and comparisons of the
promoter regions of both GA733-1 and GA733-2 genes, Linnenbach et al.
(1993) concluded that the GA33-1 gene was formed by the retroposition of
the GA733-2 gene via an mRNA intermediate.

MAPPING

Linnenbach et al. (1993) mapped the GA733-1 gene to either 1p32-p31 or
to 1p13-q12 using of human/rodent somatic cell hybrid analysis. By FISH,
Calabrese et al. (2001) mapped the TACSTD2 gene to 1p32.

MOLECULAR GENETICS

Using linkage analysis, Tsujikawa et al. (1999) mapped gelatinous
drop-like corneal dystrophy (GDLD; 204870) to a 400-kb critical region
that included M1S1. Expression analysis indicated that M1S1 is expressed
in the cornea as well as in kidney, lung, placenta, pancreas, and
prostate. All 26 affected members of 20 Japanese families were found to
be homozygotes or compound heterozygotes for 4 mutations: gln118 to ter
(Q118X; 137290.0001), gln207 to ter (Q207X; 137290.0002), ser170 to ter
(S170X; 137290.0003), and 632delA (137290.0004). The Q118X mutation
accounted for 33 of 40 (82.5%) of disease alleles. Protein expression
analysis revealed aggregation of the mutated, truncated protein in the
perinuclear region, whereas the normal protein was distributed diffusely
in the cytoplasm with a homogeneous or fine granular pattern.

Ren et al. (2002) extended molecular studies of GDLD to patients with
diverse ethnic backgrounds. They performed linkage analyses in 8
unrelated GDLD families from India, the U.S., Europe, and Tunisia. In 7
of these families, the disease locus mapped to a 16-cM interval on the
short arm of chromosome 1 that included the region of the M1S1 gene. In
addition, a 1.2-kb fragment containing the entire coding region of the
M1S1 gene was sequenced in affected individuals. Seven novel mutations
were identified in 6 families and 2 unrelated individuals. No sequence
abnormalities were detected in a single family in which the GDLD locus
was also excluded from the M1S1 region by linkage analysis. These
findings demonstrated allelic and locus heterogeneity for GDLD.

JUN

dbSNP name	rs2760499(G,C); rs4647011(C,A); rs2811894(T,G); rs1407816(G,C)
cytoBand name	1p32.1
EntrezGene GeneID	3725
EntrezGene Description	jun proto-oncogene
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR5
snpEff Effect	utr_5_prime
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.0404

*OMIM Information*

OMIM Clinical Significance

Eyes:
Progressive ophthalmoplegia

Mouth:
Scrotal tongue

Neuro:
Mental retardation

Inheritance:
Autosomal dominant

OMIM Title
*165160 V-JUN AVIAN SARCOMA VIRUS 17 ONCOGENE HOMOLOG; JUN
;;ONCOGENE JUN
ACTIVATOR PROTEIN 1, INCLUDED; AP1, INCLUDED;;
ENHANCER-BINDING PROTEIN AP1, INCLUDED

OMIM Description

DESCRIPTION

The oncogene JUN is the putative transforming gene of avian sarcoma
virus 17; it appears to be derived from a gene of the chicken genome and
has homologs in several other vertebrate species. (The name JUN comes
from the Japanese 'ju-nana,' meaning the number 17.) JUN was originally
thought to be identical to the transcription factor AP1. However, it is
now known that AP1 is not a single protein, but constitutes a group of
related dimeric basic region-leucine zipper proteins that belong to the
JUN, FOS (164810), MAF (177075), and ATF (see 603148) subfamilies. The
various dimers recognize either 12-O-tetradecanoylphorbol-13-acetate
(TPA) response elements or cAMP response elements. JUN is the most
potent transcriptional activator in its group, and its transcriptional
activity is attenuated and sometimes antagonized by JUNB (165161). For a
review of the structure and function of the AP1 transcription complexes,
see Shaulian and Karin (2002).

CLONING

Bohmann et al. (1987) isolated the human protooncogene JUN and found
that the deduced amino acid sequence is more than 80% identical to that
of the viral protein. Expression of cloned cDNA in bacteria produced a
protein with sequence-specific DNA-binding properties identical to the
phorbol ester-inducible enhancer-binding protein AP1. Antibodies raised
against 2 distinct peptides derived from JUN reacted specifically with
human AP1. In addition, partial amino acid sequence of purified AP1
revealed tryptic peptides in common with the JUN protein. Nucleotide
sequence analysis indicated that the COOH-terminus of JUN is similar to
the corresponding part of a yeast transcriptional activator.

Hattori et al. (1988) isolated a genomic clone of human JUN and
determined its primary structure and transcription pattern. Transfection
experiments showed that the cloned gene is functional, as it encodes a
trans-acting factor that stimulates transcription of an AP1-dependent
reporter gene.

GENE FUNCTION

Lamph et al. (1988) investigated regulation of murine c-jun gene
transcription and found that both serum and phorbol-ester TPA induced
c-jun gene expression.

Marx (1988) reviewed information indicating that the protein encoded by
the JUN gene acts directly to activate gene transcription in response to
cell stimulation; that the product of the FOS oncogene cooperates with
the JUN product in fostering gene transcription; that there is a
structural and functional similarity between JUN and GCN4, which induces
the activity of a large set of genes needed for amino acid synthesis in
yeast; that specifically both have a DNA-binding domain on the carboxyl
end essential for the activation of genes; that the JUN and FOS proteins
are held together in a complex by a leucine zipper; and that there are
other JUN genes in addition to the original one.

Shaulian et al. (2000) found that in mouse fibroblasts, Jun was
necessary for cell cycle reentry of ultraviolet (UV)-irradiated cells
but did not participate in the response to ionizing radiation. Cells
lacking Jun underwent prolonged cell cycle arrest but resisted
apoptosis, whereas cells that expressed Jun constitutively did not
arrest and undergo apoptosis. This function of Jun was exerted through
negative regulation of p53 (191170) association with the p21 (116899)
promoter. Cells lacking Jun exhibited prolonged p21 induction, whereas
constitutive Jun inhibited UV-mediated p21 induction.

Whitfield et al. (2001) noted that apoptosis induced in rat sympathetic
neurons by nerve growth factor (NGF; see 162030) withdrawal can be
blocked by inhibitors of RNA and protein synthesis. They presented
experimental evidence that activation of the JNK (see 601158)/JUN
pathway and increased expression of BIM (603827) are key events required
for cytochrome c release and apoptosis following NGF withdrawal.

Sphingosylphosphocholine (SPC) is a deacylated derivative of
sphingomyelin known to accumulate in Niemann-Pick disease type A
(257200). SPC is a potent mitogen that increases intracellular free
Ca(2+) and free arachidonate through pathways that are only partly
protein kinase C-dependent. Berger et al. (1995) showed that SPC
increases specific DNA-binding activity of transcription activator AP1
in electrophoretic mobility-shift assays.

Using a Drosophila model synapse, Sanyal et al. (2002) analyzed cellular
functions and regulation of the immediate-early transcription factor
AP1, a heterodimer of the basic leucine zipper proteins FOS and JUN.
They observed that AP1 positively regulates synaptic strength and
synapse number, thus showing a greater range of influence than CREB
(123810). Observations from genetic epistasis and RNA quantification
experiments indicate that AP1 acts upstream of CREB, regulates levels of
CREB mRNA, and functions at the top of the hierarchy of transcription
factors known to regulate long-term plasticity. A JUN-kinase signaling
module provided a CREB-independent route for neuronal AP1 activation;
thus, CREB regulation of AP1 expression may, in some neurons, constitute
a positive feedback loop rather than the primary step in AP1 activation.

Mathas et al. (2002) found AP1 constitutively activated, with robust JUN
and JUNB overexpression, in all cell lines derived from patients with
classical Hodgkin lymphoma (236000) and anaplastic large cell lymphoma
(ALCL), but not in other lymphoma types. AP1 supported proliferation of
Hodgkin cells, but suppressed apoptosis of ALCL cells. Mathas et al.
(2002) noted that, whereas JUN is upregulated by an autoregulatory
process, JUNB is under the control of nuclear factor kappa-B (NFKB;
164011). They found that AP1 and NFKB cooperate and stimulate expression
of the cell cycle regulator cyclin D2 (123833), the protooncogene MET
(164860), and the lymphocyte homing receptor CCR7 (600242), which are
all strongly expressed in primary Hodgkin/Reed-Sternberg (HRS) cells.

Wertz et al. (2004) reported that human DET1 (608727) promotes
ubiquitination and degradation of the protooncogenic transcription
factor c-Jun by assembling a multisubunit ubiquitin ligase containing
DNA damage-binding protein-1 (DDB1; 600045), cullin 4A (CUL4A; 603137),
regulator of cullins-1 (ROC1; 603814), and constitutively
photomorphogenic-1 (COP1; 608067). Ablation of any subunit by RNA
interference stabilized c-Jun and increased c-Jun-activated
transcription. Wertz et al. (2004) concluded that their findings
characterized a c-Jun ubiquitin ligase and define a specific function
for DET1 in mammalian cells.

JUN and N-terminal kinases (JNK) are essential for neuronal microtubule
assembly and apoptosis. Phosphorylation of the activating protein 1
(AP1) transcription factor c-Jun, at multiple sites within its
transactivation domain, is required for JNK-induced neurotoxicity.
Nateri et al. (2004) reported that in neurons the stability of c-Jun is
regulated by the E3 ligase SCF(Fbw7) (FBXW7; 606278), which
ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.
Fbxw7 depletion resulted in accumulation of phosphorylated c-Jun,
stimulation of AP1 activity, and neuronal apoptosis. SCF-7 therefore
antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling,
allowing neurons to tolerate potentially neurotoxic JNK activity.

Fang and Kerppola (2004) found evidence that JUN proteins ubiquitinated
by ITCH (606409) are targeted to lysosomes for degradation. Mutation of
the ITCH recognition motif in the N terminus of JUN eliminated its
ubiquitination and increased its stability.

Ikeda et al. (2004) generated transgenic mice expressing
dominant-negative c-Jun specifically in the osteoclast lineage and found
that they developed severe osteopetrosis due to impaired
osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited
soluble RANKL (602642)-induced osteoclast differentiation in vitro.
Overexpression of nuclear factor of activated T cells 1 (NFATC2; 600490)
or NFATC1 (600489) promoted differentiation of osteoclast precursor
cells into tartrate-resistant acid phosphatase-positive (TRAP-positive)
multinucleated osteoclast-like cells even in the absence of RANKL. These
osteoclastogenic activities of NFAT were abrogated by overexpression of
dominant-negative c-Jun. Ikeda et al. (2004) concluded that c-Jun
signaling in cooperation with NFAT is crucial for RANKL-regulated
osteoclast differentiation.

Gao et al. (2004) found in the case of c-JUN and JUNB that extracellular
stimuli modulate protein turnover by regulating the activity of an E3
ligase by means of its phosphorylation. Activation of the Jun
amino-terminal kinase (JNK; see 601158) mitogen-activated protein kinase
(MAPK) cascade after T cell stimulation accelerated degradation of c-JUN
and JUNB through phosphorylation-dependent activation of the E3 ligase
ITCH. Gao et al. (2004) found that this pathway modulates cytokine
production by effector T cells.

Nateri et al. (2005) showed that phosphorylated c-JUN interacts with the
HMG-box transcription factor TCF4 (TCF7L2; 602228) to form a ternary
complex containing c-JUN, TCF4, and beta-catenin (see 116806). Chromatin
immunoprecipitation assays revealed JNK-dependent c-JUN-TCF4 interaction
on the c-JUN promoter, and c-JUN and TCF4 cooperatively activated the
c-JUN promoter in reporter assays in a beta-catenin-dependent manner. In
the Apc(Min) mouse model of intestinal cancer (see 611731), genetic
abrogation of c-JUN N-terminal phosphorylation or gut-specific
conditional c-JUN inactivation reduced tumor number and size and
prolonged life span. Therefore, Nateri et al. (2005) concluded that the
phosphorylation-dependent interaction between c-JUN and TCF4 regulates
intestinal tumorigenesis by integrating JNK and APC/beta-catenin, 2
distinct pathways activating WNT signaling.

Koyama-Nasu et al. (2007) showed that FBL10 (FBXL10; 609078) interacted
with JUN and repressed JUN-mediated transcription in human cell lines.
Chromatin immunoprecipitation assays demonstrated that FBL10 was present
at the JUN promoter and that JUN was required for recruitment of FBL10.
FBL10 bound unmethylated CpG sequences in the JUN promoter through its
CxxC zinc finger and tethered transcriptional repressor complexes.
Suppression of FBL10 expression by RNA interference induced
transcription of JUN and JUN target genes and caused aberrant cell cycle
progression and increased UV-induced cell death. Furthermore, FBL10
protein and mRNA were downregulated in response to UV in an inverse
correlation with JUN. Koyama-Nasu et al. (2007) concluded that FBL10 is
a key regulator of JUN function.

Aguilera et al. (2011) demonstrated that unphosphorylated, but not
N-terminally phosphorylated, c-Jun interacts with MBD3 (603573) and
thereby recruits the nucleosome remodeling and histone acetylation
(NuRD) repressor complex. MBD3 depletion in colon cancer cells increased
histone acetylation at AP1-dependent promoters, which resulted in
increased target gene expression. The intestinal stem cell marker LGR5
(606667) was identified as a novel target gene controlled by c-Jun/MBD3.
Gut-specific conditional deletion of Mbd3 in mice stimulated c-Jun
activity and increased progenitor cell proliferation. In response to
inflammation, Mbd3 deficiency resulted in colonic hyperproliferation,
and Mbd3 gut-null mice showed markedly increased susceptibility to
colitis-induced tumorigenesis. Aguilera et al. (2011) noted that
concomitant inactivation of a single allele of c-Jun reverted
physiologic and pathologic hyperproliferation, as well as the increased
tumorigenesis in Mbd3 gut-null mice. Thus, the transactivation domain of
c-Jun recruits MBD3/NuRD to AP1 target genes to mediate gene repression,
and this repression is relieved by JNK (601158)-mediated c-Jun
N-terminal phosphorylation.

Using chromatin immunoprecipitation sequencing in T-helper-17 (TH17)
cells, Glasmacher et al. (2012) found that IRF4 (601900) targets
sequences enriched for AP1-IRF composite elements (AICEs) that are
cobound by BATF (612476), an AP1 factor required for TH17, B, and
dendritic cell differentiation. IRF4 and BATF bind cooperatively to
structurally divergent AICEs to promote gene activation and TH17
differentiation. The AICE motif directs assembly of IRF4 or IRF8
(601565) with BATF heterodimers and is also used in TH2, B, and
dendritic cells. Glasmacher et al. (2012) concluded that this genomic
regulatory element and cognate factors appear to have evolved to
integrate diverse immunomodulatory signals.

GENE STRUCTURE

Hattori et al. (1988) determined that the JUN gene has no introns.

MAPPING

Haluska et al. (1988) isolated a genomic DNA clone encompassing the JUN
gene and used it to determine the chromosomal location. Southern blot
analysis of a rodent-human somatic cell hybrid panel indicated that JUN
is situated on 1p. In situ hybridization narrowed the assignment to
1p32-p31, a chromosomal region involved in both translocations and
deletions in human malignancies. By in situ hybridization, Hattori et
al. (1988) mapped JUN to 1p32-p31.

Mattei et al. (1990) mapped the mouse homolog to chromosome 4. Bahary et
al. (1991) presented molecular genetic linkage maps of mouse chromosome
4 which established the breakpoints in the mouse 4/human 1p region of
homology to a 2-cM interval between Ifa and Jun in mouse and to the
interval between JUN and ACADM (607008) in the human.

ANIMAL MODEL

Hilberg et al. (1993) developed Jun-null mice by gene targeting.
Heterozygous mutant mice appeared normal, but embryos lacking Jun died
between midgestation and late gestation and exhibited impaired
hepatogenesis, altered fetal liver erythropoiesis, and generalized
edema. Jun-defective embryonic stem cells were able to participate in
the development of all somatic cells in chimeric mice except liver
cells, indicating an essential function of Jun in hepatogenesis.

By alanine substitution of ser63 and ser73 of mouse Jun, Behrens et al.
(1999) demonstrated that phosphorylation on these residues was required
for several apoptotic functions. Mouse fibroblasts carrying mutated Jun
had proliferation- and stress-induced apoptotic defects accompanied by
reduced AP1 activity. Mutant mice were smaller than controls, and they
were resistant to epileptic seizures and neuronal apoptosis induced by
the excitotoxic amino acid kainate. Primary mutant neurons were also
protected from apoptosis.

Eferl et al. (2003) used liver-specific inactivation of Jun at different
stages of tumor development to study its role in chemically induced
hepatocellular carcinomas (HCCs) in mice. The requirement for Jun was
restricted to early stages of tumor development, and the number and size
of hepatic tumors was dramatically reduced when Jun was inactivated
after the tumor had initiated. The impaired tumor development correlated
with increased levels of p53 and its target gene Noxa (PMAIP1; 604959),
resulting in the induction of apoptosis without affecting cell
proliferation. Primary hepatocytes lacking Jun showed increased
sensitivity to tumor necrosis factor-alpha (TNF; 191160)-induced
apoptosis, which was abrogated in the absence of p53. These data
indicated that JUN prevents apoptosis by antagonizing p53 activity,
illustrating a mechanism that might contribute to the early stages of
human HCC development.

MGC34796

dbSNP name	rs7554821(G,A); rs7532243(A,C); rs74076108(G,A); rs7532358(A,G); rs1061882(A,C); rs138477680(G,C); rs6587940(T,C); rs6700526(T,C); rs111412799(C,T); rs6587941(G,A)
cytoBand name	1p31.3
EntrezGene GeneID	414927
snpEff Gene Name	RP11-430G17.1
EntrezGene Description	sepiapterin reductase (7,8-dihydrobiopterin:NADP+ oxidoreductase) pseudogene
EntrezGene Type of gene	pseudo
Annovar Region type	ncRNA_exonic
snpEff Effect	transcript
snpEff Functional Class	none
snpEff Gene Biotype	processed_pseudogene
snpEff Impact	modifier
dbSNP GMAF	0.3095

FOXD3

dbSNP name	rs6588025(T,C)
cytoBand name	1p31.3
EntrezGene GeneID	27022
EntrezGene Description	forkhead box D3
EntrezGene Type of gene	protein-coding
Annovar Region type	UTR3
snpEff Effect	utr_3_prime
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.2213

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Cardiomyopathy, right ventricular;
Fibrofatty replacement of right ventricular myocardium;
Ventricular arrhythmia (sustained VT);
Syncope

SKIN, NAILS, HAIR:
[Skin];
Normal skin (no palmoplantar keratoderma);
[Hair];
Normal hair (no woolly hair)

MISCELLANEOUS:
Genetic heterogeneity;
Allelic to Naxos disease (601214)

MOLECULAR BASIS:
Caused by mutation in the junction plakoglobin gene (JUP, 173325.0002).

OMIM Title
*611539 FORKHEAD BOX D3; FOXD3
;;HFH2;;
GENESIS, MOUSE, HOMOLOG OF

OMIM Description

CLONING

Sutton et al. (1996) cloned mouse Foxd3, which they called Genesis due
to its exclusive expression in primitive cells, from an embryonal
carcinoma cDNA library. The deduced 465-amino acid protein contains a
100-amino acid central winged helix domain and several domains and
motifs found in transcriptional regulators. Northern blot analysis
detected Genesis expression in mouse embryonic stem cells and embryonal
carcinoma cells, but not in other embryonic, neonatal, or adult tissues
or cells examined. Differentiation of mouse embryonal carcinoma cells
and mouse embryonic stem cells in culture led to downregulation of
Genesis expression.

Hanna et al. (2002) noted that FOXD3 is expressed during early
embryogenesis in the epiblast and later in neural crest cells, and that
FOXD3 expression is a diagnostic marker of human embryonic stem cell
lines. Using RT-PCR, they found that mouse Foxd3 was not expressed in
unfertilized oocytes or fertilized 1-cell embryos, but it was expressed
in blastocyst-stage embryos. In situ hybridization detected Foxd3
throughout the epiblast of 6.5-day postcoitum embryo, with faint
expression in the extraembryonic region.

MAPPING

By interspecific backcross analysis, Sutton et al. (1996) mapped the
mouse Foxd3 gene to a region of chromosome 4 that shares homology of
synteny with human chromosome 1p31.

GENE FUNCTION

Sutton et al. (1996) found that mouse Genesis bound to AT-rich sequences
and showed highly specific binding to the E2 stem cell enhancer.
Cotransfection assays revealed that Genesis repressed reporter gene
expression in a dose-dependent manner in embryonic kidney cells and HeLa
cells.

Guo et al. (2002) showed that mammalian Foxd3 and Oct4 (POU5F1; 164177)
bound identical regulatory DNA sequences in the osteopontin (SPP1;
166490) promoter. Oct4 interacted directly with Foxd3, and both proteins
activated the osteopontin promoter, either alone or in combination.
Foxd3 also activated the Foxa1 (602294) and Foxa2 (600288) promoters,
and coexpression of Oct4 inhibited Foxd3-mediated activation of these
promoters.

MOLECULAR GENETICS

In affected members of a large family with autosomal dominant vitiligo
(see AIS1; 607836), Alkhateeb et al. (2005) identified a heterozygous
mutation in the promoter region of the FOXD3 gene (611539.0001). The
authors noted that FOXD3 is a regulator of melanoblast differentiation
and suggested that increased transcriptional activity conferred by the
promoter variant may suppress or alter the differentiation of
melanoblasts in these patients.

ANIMAL MODEL

Hanna et al. (2002) found that Foxd3 -/- mouse embryos died after
implantation at approximately 6.5 days postcoitum with loss of epiblast
cells, expansion of proximal extraembryonic tissues, and a distal,
mislocalized anterior organizing center. Chimera analysis revealed that
Foxd3 function was required in the epiblast and that Foxd3 -/- embryos
could be rescued by a small number of wildtype cells. Foxd3 -/-
blastocysts appeared morphologically normal and expressed Oct4, Sox2
(184429), and Fgf4 (164980), but when placed in vitro, the inner cell
mass proliferated initially and then failed to expand. Hanna et al.
(2002) concluded that FOXD3 is required for maintenance of progenitor
cells in the embryo.

MIR4794

dbSNP name	rs17126710(C,T)
ccdsGene name	CCDS628.2
cytoBand name	1p31.3
EntrezGene GeneID	100616338
snpEff Gene Name	CACHD1
EntrezGene Description	microRNA 4794
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.0225
ExAC AF	0.006524

MIR3671

dbSNP name	rs147004258(C,T); rs521188(A,G)
cytoBand name	1p31.3
EntrezGene GeneID	101927106
EntrezGene Symbol	LOC101927106
snpEff Gene Name	MIR101-1
EntrezGene Description	uncharacterized LOC101927106
EntrezGene Type of gene	miscRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	miRNA
snpEff Impact	modifier
dbSNP GMAF	9.183E-4

SNORD45B

dbSNP name	rs11161620(G,A)
ccdsGene name	CCDS669.1
cytoBand name	1p31.1
EntrezGene GeneID	26804
snpEff Gene Name	ACADM
EntrezGene Description	small nucleolar RNA, C/D box 45B
EntrezGene Type of gene	snoRNA
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.1671
ESP Afr MAF	0.13984
ESP All MAF	0.224451
ESP Eur/Amr MAF	0.261678
ExAC AF	0.202,8.339e-06

COL24A1

dbSNP name	rs1047895(C,T); rs1047893(T,C); rs1047892(A,C); rs17128149(T,C); rs12564080(A,C); rs12067749(T,C); rs2389973(T,C); rs145625932(C,T); rs76710587(C,T); rs1481200(C,T); rs12037785(C,A); rs61783080(G,A); rs7528385(A,G); rs79033646(A,G); rs114069383(T,C); rs4379699(T,A); rs6686719(T,C); rs2389974(C,T); rs2389975(C,G); rs12756365(A,G); rs12756841(G,A); rs6576788(T,C); rs6576789(G,A); rs143474342(A,G); rs7529942(C,A); rs7532758(C,T); rs7554621(G,A); rs7544908(A,G); rs7535884(C,T); rs6682235(C,T); rs2014750(A,T); rs2014733(A,T); rs10873718(C,G); rs10873719(G,A); rs12128916(A,T); rs7547023(G,A); rs10747324(G,A); rs6673975(C,T); rs77796844(C,T); rs399547(C,T); rs432254(C,T); rs450953(G,C); rs420515(C,T); rs2785081(G,A); rs414618(G,A); rs369999(G,A); rs381453(C,G); rs1813656(A,G); rs434853(A,T); rs373787(A,G); rs401657(C,A); rs438401(A,G); rs444875(A,G); rs383558(T,C); rs425357(A,T); rs430956(G,C); rs114431428(G,A); rs419409(C,G); rs424205(C,T); rs142806826(G,C); rs447446(C,T); rs429040(A,G); rs417887(G,A); rs418979(A,G); rs7521240(C,T); rs2785083(C,G); rs138939351(A,T); rs2764470(T,C); rs550329(G,A); rs77329135(T,C); rs369318(T,C); rs369314(T,C); rs17128257(A,G); rs10493775(C,T); rs392038(G,A); rs426831(T,C); rs366516(G,A); rs6698578(G,A); rs116725229(T,G); rs399514(T,C); rs12046489(T,A); rs6697548(T,C); rs450145(T,C); rs402885(G,T); rs142770795(A,G); rs61783134(G,T); rs184340(A,T); rs75371830(G,A); rs720619(A,G); rs313726(C,G); rs313727(C,T); rs17396994(A,G); rs313728(C,T); rs313729(A,T); rs77139550(C,T); rs313722(A,C); rs12562146(T,A); rs12563027(A,G); rs12075929(C,A); rs313723(C,A); rs12754358(C,T); rs313724(C,T); rs17128307(C,T); rs41331746(G,A); rs41371348(A,C); rs41289767(T,C); rs313725(A,G); rs366214(T,C); rs185076467(G,C); rs486417(C,T); rs188851164(T,C); rs313710(T,C); rs12128605(C,T); rs313711(G,A); rs12753056(G,A); rs313712(G,A); rs313713(G,A); rs11579570(A,T); rs313714(C,G); rs313715(G,T); rs313716(T,C); rs313717(T,C); rs313719(A,G); rs74097092(A,G); rs313720(G,C); rs313721(T,C); rs7539262(G,A); rs313731(T,A); rs313732(A,G); rs313733(A,G); rs193398(T,C); rs313734(T,C); rs313735(T,A); rs313736(C,T); rs191199838(G,A); rs313737(G,C); rs191470812(T,A); rs673506(A,G); rs61783136(G,A); rs432168(G,A); rs380654(C,G); rs414143(G,C); rs366187(G,A); rs76408018(C,T); rs1977331(T,C); rs598104(A,T); rs72950669(C,T); rs412328(G,T); rs12727784(A,G); rs190084664(T,C); rs449901(T,C); rs151255686(C,T); rs6677315(G,C); rs313738(C,A); rs187287483(G,A); rs313739(T,C); rs167518(T,C); rs313740(G,A); rs10159046(T,C); rs313741(A,T); rs12239978(C,T); rs313742(C,T); rs10158651(G,T); rs6576790(C,T); rs313744(G,A); rs172694(G,A); rs313745(G,T); rs11161677(C,T); rs78726658(G,A); rs313746(A,G); rs313747(G,A); rs313756(C,T); rs10873722(T,C); rs11161678(T,C); rs313757(C,A); rs313758(A,G); rs313759(T,G); rs78426121(G,A); rs6698633(T,C); rs12091583(C,A); rs313760(G,A); rs6576791(T,A); rs6576792(C,T); rs186376(G,T); rs6693669(C,T); rs186980825(G,A); rs1481199(G,A); rs1842579(C,T); rs6697619(T,C); rs313748(A,T); rs313762(C,G); rs313761(G,C); rs7535390(G,A); rs6661124(C,T); rs34635832(T,A); rs6676346(T,A); rs10873723(C,A); rs12727916(T,C); rs6665363(T,A); rs12760458(A,C); rs12077825(G,A); rs12098168(C,T); rs12088004(A,C); rs172693(T,C); rs11161686(C,T); rs1325260(A,G); rs72952531(G,A); rs11161687(T,C); rs313705(G,A); rs4912446(G,A); rs313706(T,C); rs10873725(T,A); rs980054(T,C); rs313698(G,T); rs313699(G,T); rs112710367(T,C); rs184339(G,T); rs4912437(C,A); rs313700(G,A); rs2297744(A,G); rs1010058(C,A); rs313701(A,T); rs115578936(T,C); rs313702(C,T); rs313703(T,C); rs313704(T,A); rs6576793(C,T); rs7530839(C,T); rs1962482(G,T); rs80059966(C,T); rs72952543(G,A); rs6695874(A,G); rs2170331(G,A); rs313707(A,G); rs11161689(C,T); rs12033218(C,T); rs313708(A,G); rs11161691(A,G); rs313709(T,C); rs556247(G,A); rs12091504(G,A); rs75241249(G,A); rs435007(T,A); rs428475(T,A); rs12124109(A,G); rs1904947(C,T); rs61785081(G,A); rs113318459(C,G); rs629140(G,C); rs383588(G,A); rs445782(G,A); rs6657706(C,T); rs437257(G,A); rs188559024(C,T); rs1871763(G,A); rs183188257(C,T); rs313763(C,T); rs12759687(T,C); rs186063872(T,C); rs313764(A,G); rs190756234(A,T); rs7523196(T,C); rs79843903(G,A); rs7520948(A,C); rs7554796(C,T); rs79683227(G,A); rs313765(A,C); rs313766(C,T); rs313767(A,G); rs11161692(C,T); rs188763(A,G); rs2256515(T,G); rs2795038(C,T); rs313768(C,G); rs313769(T,C); rs12119433(G,C); rs313770(A,G); rs313771(T,C); rs313772(T,C); rs313773(A,G); rs313774(A,G); rs313775(T,A); rs17411495(T,C); rs11161693(T,C); rs12029238(T,C); rs7544141(G,A); rs115406208(A,G); rs114937096(C,A); rs115646722(G,A); rs7549218(T,C); rs11161695(G,T); rs10873731(G,A); rs11161696(G,T); rs72952569(T,C); rs12136023(C,A); rs1564518(T,C); rs1564517(G,A); rs7524286(C,T); rs2086495(G,T); rs1564516(T,C); rs1564515(A,G); rs7536101(A,G); rs12122234(G,A); rs11161697(A,G); rs12735496(T,A); rs12739425(T,C); rs12739620(T,G); rs12725203(A,G); rs12725350(A,G); rs2892901(T,G); rs11161698(G,A); rs1072508(A,G); rs1072509(C,A); rs12740827(A,G); rs12740836(A,T); rs35841238(T,G); rs12144570(C,T); rs2170333(T,C); rs12757388(C,T); rs181016821(A,C); rs12755267(T,C); rs6701281(T,G); rs7542433(C,A); rs7556366(T,C); rs112826747(A,G); rs12727503(T,G); rs11589722(C,A); rs10732722(A,G); rs12732365(T,C); rs6671033(G,A); rs183828669(T,C); rs151195339(C,T); rs187387365(A,G); rs1965928(G,A); rs113094868(G,A); rs112245942(C,T); rs74679611(A,T); rs4912448(G,A); rs35545564(G,A); rs72712703(A,G); rs12726975(T,C); rs72712704(C,T); rs7512136(G,A); rs12746617(T,C); rs74378859(C,T); rs4912449(C,T); rs7541806(C,G); rs184802021(G,A); rs192265505(C,T); rs12133355(G,A); rs59056351(A,C); rs729102(A,G); rs12088838(T,C); rs2047788(A,G); rs142230937(A,G); rs1604568(A,G); rs1604567(T,C); rs72952597(G,T); rs11812027(A,G); rs143821366(C,T); rs10873732(A,G); rs75739884(C,T); rs146865780(A,T); rs181677382(G,A); rs10493776(T,G); rs138147770(T,C); rs1858556(T,C); rs12753255(A,C); rs1481202(G,A); rs17128475(A,C); rs10873734(A,G); rs997439(A,C); rs146900574(C,T); rs12568820(T,C); rs4146294(C,T); rs1481201(T,C); rs1502657(C,G); rs41306625(G,A); rs10493777(C,T); rs12747420(G,A); rs61785115(T,C); rs11161709(C,T); rs6703317(G,A); rs12752474(C,A); rs12734458(T,C); rs6703454(G,A); rs4486475(T,C); rs12043396(T,A); rs12568614(A,G); rs12120918(C,T); rs116258726(C,T); rs149173721(C,A); rs12136742(G,A); rs12567016(G,T); rs11161710(T,A); rs6702912(G,A); rs10782561(G,A); rs184361430(A,T); rs140606362(G,A); rs6695598(A,T); rs12755099(T,C); rs10873736(A,T); rs7516144(G,A); rs4912450(A,G); rs72712740(T,G); rs148912389(C,T); rs12564780(C,T); rs12564781(C,G); rs4272649(C,T); rs186778152(T,C); rs148454576(T,C); rs2174051(G,A); rs188537000(C,G); rs147078635(A,G); rs74511078(C,A); rs7556117(T,G); rs67487620(G,C); rs28571037(G,A); rs12407664(C,A); rs12740695(T,A); rs12759079(C,T); rs61785119(T,C); rs7526013(T,C); rs7512039(C,T); rs12751687(T,A); rs34589269(G,T); rs12742187(C,G); rs56301284(C,G); rs6673508(C,T); rs6699709(G,A); rs79159470(T,C); rs12032751(T,C); rs12745489(T,C); rs1112328(T,C); rs1112327(G,C); rs115430248(T,C); rs1112326(T,C); rs1587675(A,G); rs148387130(G,A); rs11161711(C,T); rs180840846(G,A); rs185785251(C,T); rs12723176(C,T); rs7554463(G,T); rs7512890(G,A); rs7536689(C,A); rs603297(A,C); rs1359415(C,T); rs605060(G,A); rs1354245(G,A); rs12240129(C,T); rs76633767(G,A); rs606432(A,C); rs1698733(C,A); rs75650273(A,T); rs72712775(T,C); rs861933(G,A); rs4303095(T,C); rs79263818(A,T); rs4912438(C,G); rs524192(G,A); rs597330(T,C); rs499518(T,C); rs145683647(C,T); rs186531231(A,G); rs578615(A,G); rs6666627(G,A); rs77615990(T,C); rs72712786(A,T); rs658934(A,T); rs483498(C,T); rs188399367(G,T); rs6665006(T,C); rs12411184(C,T); rs560876(C,T); rs631632(A,G); rs72712794(A,G); rs189840789(A,G); rs35826410(C,T); rs72712798(T,C); rs180852183(T,C); rs12740060(T,C); rs486726(A,G); rs72712801(G,A); rs116045312(G,A); rs606678(G,C); rs12401802(C,G); rs12751341(T,C); rs12736249(C,T); rs686272(C,T); rs10493778(G,T); rs17404261(T,C); rs559247(C,T); rs182556280(C,T); rs12747217(C,T); rs187476242(T,C); rs7538391(T,C); rs115569806(G,T); rs4584420(A,G); rs111235134(C,T); rs625872(C,T); rs115154373(A,G); rs491358(A,G); rs573444(T,G); rs608460(C,T); rs693436(C,T); rs11803202(C,A); rs593146(G,A); rs146357607(C,T); rs1324898(G,T); rs4912440(T,G); rs533090(C,A); rs647977(C,G); rs474832(C,T); rs481277(G,T); rs681639(T,C); rs570288(G,T); rs141892706(G,A); rs489141(A,G); rs607336(T,C); rs522075(C,T); rs1853735(C,T); rs72714031(A,G); rs591634(C,A); rs556848(G,A); rs12405568(C,T); rs77480927(C,T); rs472286(T,G); rs682964(C,T); rs668874(G,T); rs188613663(G,C); rs10493780(C,T); rs633028(C,G); rs537408(T,C); rs35556419(G,T); rs537550(C,T); rs1359421(G,A); rs10493782(A,G); rs482789(C,T); rs482981(T,C); rs11799965(T,G); rs589698(C,T); rs144221275(G,A); rs518829(A,C); rs17413395(G,C); rs652321(C,T); rs472154(G,C); rs115866531(A,G); rs6656538(C,T); rs6672098(T,C); rs4912453(T,C); rs9988431(G,A); rs4912454(A,G); rs4306156(A,T); rs4272648(C,T); rs4350224(G,A); rs80133350(T,A); rs2390005(T,G); rs12134342(C,T); rs2390006(T,G); rs2390007(G,A); rs2390008(T,C); rs6576794(T,A); rs6576795(C,T); rs6676497(A,C); rs12127813(A,G); rs12120406(G,A); rs61617423(G,A); rs12025292(G,A); rs75952756(T,C); rs12039529(C,T); rs6704536(G,A); rs77024527(A,T); rs7537787(C,T); rs7551636(T,A); rs687776(T,C); rs7514604(G,A); rs12025755(T,C); rs12029153(A,G); rs11161713(A,G); rs11161714(T,C); rs11161715(A,G); rs12118004(G,A); rs12403155(T,G); rs6703296(A,G); rs12031047(A,G); rs12027751(T,G); rs12023979(G,A); rs12031105(A,G); rs12031129(A,C); rs7516083(T,C); rs7547149(C,T); rs10873740(T,C); rs142746940(C,T); rs79947224(C,T); rs11161717(A,G); rs12125053(T,C); rs12135956(C,T); rs55904692(A,C); rs55892290(T,C); rs55958413(C,A); rs56278817(T,C); rs17405077(A,G); rs17405097(T,C); rs17405131(T,C); rs12040977(C,T); rs12040981(C,T); rs663463(G,A); rs663901(T,C); rs664412(T,C); rs511363(A,T); rs17128656(A,T); rs676973(G,T); rs17413771(C,T); rs582517(A,G); rs139666759(T,G); rs567617(A,C); rs584883(T,C); rs584895(T,C); rs585708(A,G); rs586240(G,T); rs535637(A,G); rs599761(G,A); rs9701002(C,A); rs12079919(A,G); rs79832745(C,T); rs532684(A,C); rs612256(C,T); rs77225202(G,T); rs613060(T,C); rs11161719(T,C); rs77218022(A,G); rs615805(T,C); rs616281(T,C); rs500756(T,A); rs617652(G,T); rs617653(T,G); rs477562(C,T); rs368915304(G,A); rs6576798(T,C); rs471070(C,T); rs631512(C,A); rs580540(G,A); rs74793007(T,G); rs368622332(G,C); rs1324899(C,T); rs521253(G,A); rs519361(C,A); rs518538(A,C); rs635397(C,T); rs516799(G,A); rs648833(C,T); rs489385(A,G); rs61783511(A,G); rs489267(A,G); rs650216(G,A); rs662369(T,C); rs570172(A,G); rs664099(T,C); rs569409(C,T); rs567565(T,G); rs4912455(A,G); rs632295(C,T); rs632697(A,G); rs538256(G,T); rs634946(T,C); rs635391(C,T); rs635713(T,G); rs636210(T,C); rs511732(G,T); rs647380(T,C); rs648866(T,A); rs574780(C,T); rs551670(G,C); rs80160804(A,G); rs6687775(T,C); rs679256(C,A); rs547023(G,A); rs680179(T,C); rs521314(T,C); rs1629358(C,T); rs1698734(T,C); rs78716972(A,G); rs1698735(C,T); rs116144332(T,G); rs1359419(T,A); rs514185(A,G); rs589343(T,C); rs489325(A,G); rs600184(G,A); rs486680(C,T); rs601167(G,C); rs6679444(T,C); rs80261525(C,T); rs565639(C,T); rs616715(T,A); rs618555(T,C); rs191765683(C,T); rs505589(G,A); rs629683(C,T); rs629719(A,G); rs17405393(C,T); rs1698736(C,T); rs2390050(T,C); rs201609975(T,C); rs631054(C,T); rs501058(G,A); rs7525617(C,T); rs631935(C,A); rs477862(G,A); rs633604(C,T); rs7547855(G,T); rs7526060(C,T); rs474106(C,T); rs473232(T,C); rs557928(A,T); rs10493787(G,C); rs648355(G,A); rs648366(A,G); rs115186110(T,C); rs10518362(T,C); rs673928(C,G); rs12564959(T,A); rs78447538(G,A); rs494796(A,G); rs1698737(T,C); rs61800686(A,G); rs373880518(G,A); rs113035681(A,G); rs78713898(C,T); rs72716124(T,A); rs569419(T,A); rs61800687(C,T); rs56353901(T,C); rs143101162(T,C); rs541936(T,C); rs6691400(C,T); rs540159(T,C); rs11161721(C,A); rs516213(G,A); rs641712(G,A); rs367693606(G,A); rs485816(A,G); rs74611176(A,G); rs657026(A,G); rs657540(G,T); rs658313(C,T); rs12090143(C,G); rs565860(T,C); rs564224(T,C); rs17405880(G,A); rs112043150(C,T); rs17405900(A,G); rs74415151(T,C); rs17414470(C,A); rs17414498(G,C); rs17414519(G,A); rs1408668(A,G); rs7411998(G,A); rs587650(A,G); rs138631692(C,T); rs74586485(G,T); rs77366239(G,A); rs113773847(T,A); rs113386773(C,T); rs112240590(T,C); rs116737369(G,C); rs115312089(C,T); rs114331847(C,A); rs116250534(A,G); rs112351822(C,T); rs113578298(G,T); rs111401973(T,G); rs77091281(C,T); rs546269(G,C); rs4912442(A,C); rs4912459(C,T); rs4912443(A,G); rs614895(A,G); rs113739725(C,T); rs112496575(C,T); rs517786(C,T); rs17414568(G,A); rs17128758(A,G); rs56392000(A,G); rs77928364(G,A); rs78460661(A,G); rs76052536(A,G); rs17131759(A,C); rs17414617(G,A); rs17406104(A,G); rs80225189(C,T); rs79403884(A,C); rs112850770(C,G); rs17406138(G,A); rs1998684(G,A); rs569541(A,G); rs645271(C,T); rs17406173(C,T); rs56229462(T,G); rs55766419(T,C); rs12746006(T,G); rs74455415(A,T); rs113601896(T,C); rs72716130(C,T); rs582141(C,G); rs7414042(T,C); rs582622(C,T); rs1393554(T,A); rs1408667(C,T); rs12567495(T,C); rs598471(C,T); rs61800722(A,T); rs17414884(G,A); rs555289(G,C); rs7552516(C,G); rs72716134(C,T); rs71506583(C,T); rs17406450(T,C); rs695051(A,G); rs61800724(C,T); rs1408666(C,T); rs35982302(A,G); rs12079760(G,A); rs61800725(A,G); rs72716135(A,C); rs640303(T,C); rs79824627(T,C); rs61800726(T,C); rs652837(C,T); rs75113288(C,G); rs12740195(A,T); rs61800727(T,C); rs12740502(A,G); rs17406471(T,C); rs12402809(C,T); rs12143304(A,G); rs566108(A,C); rs12408108(G,C); rs72958291(G,T); rs182802083(T,A); rs72958294(C,A); rs610639(C,T); rs17128768(A,C); rs7552025(G,A); rs17406644(T,C); rs12567549(G,T); rs476149(A,C); rs12729383(G,A); rs12729890(G,T); rs12743320(C,T); rs12743750(G,A); rs12743345(A,G); rs141231558(C,T); rs12744993(G,T); rs12748565(A,G); rs12748730(C,A); rs182750736(T,C); rs138395177(C,T); rs142870790(C,T); rs17406755(G,A); rs60891279(C,T); rs541395(G,A); rs61800728(T,A); rs6674872(C,T); rs11487918(G,A); rs4912460(T,C); rs4912445(A,G); rs61800729(C,T); rs597669(G,A); rs79718851(A,G); rs17415366(C,T); rs182144208(C,T); rs680613(C,T); rs679734(C,T); rs72960324(G,A); rs498554(A,T); rs75782849(G,T); rs6658643(A,G); rs12754643(A,G); rs551219(T,C); rs12750946(T,C); rs12730639(A,G); rs485204(G,C); rs148484669(C,T); rs12354099(C,T); rs72716141(G,A); rs56040491(T,A); rs12077017(C,G); rs116562486(A,C); rs10518360(C,T); rs555578(A,T); rs34848727(T,C); rs12057842(G,A); rs61800732(T,G); rs583315(C,T); rs689040(T,C); rs72960354(C,T); rs6682503(G,A); rs12353970(G,A); rs12736258(G,C); rs11161727(A,T); rs4522024(T,C); rs12723246(T,G); rs12742014(G,A); rs12354100(A,C); rs41313268(T,G); rs12756057(C,A); rs12097262(G,A); rs6703328(C,T); rs11806244(C,T); rs11801529(T,C); rs112891904(A,C); rs12733714(A,G); rs72716145(T,C); rs17415692(C,T); rs12755069(T,C); rs10443173(A,G); rs12071046(A,T); rs146243778(G,A); rs137990270(G,A); rs11802445(T,C); rs12744971(G,A); rs6665582(C,T); rs369118329(C,T); rs12566718(C,T); rs12566940(C,T); rs10443169(G,A); rs10873742(C,T); rs7548696(G,C); rs111943767(G,A); rs140426173(C,T); rs12564004(G,A); rs112458166(A,C); rs72716149(T,C); rs12744064(G,C); rs146550870(T,G); rs143136298(C,G); rs148239291(G,A); rs6686088(T,C); rs141037075(T,C); rs2202675(T,C); rs2221588(T,C); rs139361292(G,T); rs116434207(A,C); rs76680465(C,A); rs186083897(A,G); rs7545716(T,C); rs112583392(A,C); rs72960374(C,A); rs12752769(T,C); rs72716150(G,A); rs80240281(A,G); rs72716152(G,A); rs6699364(T,C); rs11585276(A,C); rs11588997(C,G); rs11583563(T,C); rs11583566(T,C); rs59767206(G,T); rs12725994(T,G); rs12744313(G,A); rs4912461(T,G); rs7514100(A,C); rs12754154(C,T); rs12736520(T,C); rs10873744(G,A); rs190465624(A,G); rs140389337(A,G); rs17415754(C,T); rs142086023(G,A); rs6687118(C,A); rs11161729(G,A); rs1507281(C,T); rs10782563(T,C); rs12723978(T,C); rs6665375(G,C); rs141977422(C,A); rs34168319(G,A); rs77867367(G,A); rs10493786(A,C); rs10493785(C,T); rs113978659(C,T); rs77771545(C,T); rs12405791(G,A); rs12758598(G,C); rs1507288(T,C); rs17415844(A,G); rs6682482(G,A); rs61802173(A,G); rs17407336(C,T); rs11161732(G,A); rs10782564(A,G); rs12082787(G,A); rs61802174(T,C); rs10873745(C,A); rs75393931(C,T); rs139672524(G,C); rs115077383(C,A); rs142980640(T,C); rs6691885(A,G); rs77934242(C,T); rs55729234(C,T); rs10873746(C,A); rs36035589(T,G); rs12728287(A,C); rs1336054(A,G); rs12043664(A,T); rs997110(A,C); rs112778051(G,A); rs1605417(C,G); rs1605416(C,A); rs883201(A,C); rs56237094(C,T); rs6672107(G,T); rs1828018(A,T); rs1911545(A,T); rs117558703(G,A); rs12044349(T,C); rs6670074(T,C); rs10047143(C,T); rs2390017(G,A); rs2390016(C,T); rs2390015(A,C); rs112059396(A,G); rs114128692(C,T); rs9988602(T,C); rs12029694(C,G); rs11161734(G,C); rs12742966(C,T); rs12093594(A,G); rs141605057(T,C); rs78783089(C,A); rs6665315(T,A); rs2221589(C,A); rs1395717(G,A); rs11161735(C,T); rs1360903(G,T); rs12755633(G,T); rs12142577(T,C); rs12047136(T,A); rs57251624(A,G); rs55912038(C,T); rs55713534(G,A); rs12048065(T,C); rs4912463(A,C); rs12023254(A,G); rs11161736(T,C); rs6690902(G,T); rs11161737(G,T); rs11581522(C,T); rs6576800(T,C); rs115268857(T,C); rs143962298(C,T); rs12057993(T,C); rs75653506(T,C); rs79954139(G,A); rs7550464(G,A); rs7550559(G,A); rs7550571(G,A); rs2039602(A,C); rs11161738(C,T); rs2039603(C,T); rs2039604(G,A); rs11161739(G,A); rs11161740(T,C); rs12075854(C,T); rs11161741(A,G); rs12565251(C,G); rs6686446(G,A); rs6675364(A,G); rs6678131(T,G); rs6663055(C,T); rs6675562(A,G); rs12024025(T,C); rs12048574(G,A); rs12024952(C,A); rs12742000(G,A); rs12024954(C,T); rs61802236(G,A); rs1414600(A,G); rs61802237(A,T); rs2892909(G,A); rs2390014(T,G); rs6666638(C,G); rs12402985(C,G); rs1108309(G,C); rs1507292(T,C); rs6686533(A,G); rs6697461(G,A); rs6691959(T,C); rs10873747(C,T); rs10873748(T,C); rs10873749(T,C); rs2221587(C,T); rs1336052(A,C); rs6680321(C,T); rs11161742(T,C); rs11161743(G,A); rs11161744(T,A); rs1995687(C,G); rs11161745(C,T); rs12567887(G,A); rs4556388(T,C); rs150713883(T,C); rs12049014(T,A); rs113167851(G,T); rs61802244(C,T); rs2390013(G,A); rs2390012(C,T); rs4631724(T,G); rs6690591(C,T); rs6690880(C,G); rs6703567(A,C); rs4144876(C,T); rs4144875(T,G); rs72716178(A,T); rs1948962(C,A); rs192989476(A,G); rs12118936(T,C); rs1507266(C,T); rs1507265(C,T); rs2174767(G,A); rs11161746(A,G); rs17128866(A,G); rs11161747(G,A); rs1507264(A,G); rs2202674(C,T); rs1876403(C,T); rs1507263(C,T); rs1507262(T,C); rs72716183(A,G); rs12569126(G,A); rs1999748(T,C); rs11578172(T,C); rs7521933(T,C); rs76713460(G,A); rs4379700(T,C); rs7531153(G,A); rs7531177(G,T); rs7554369(C,G); rs17408110(T,C); rs1507286(G,A); rs1507285(A,T); rs12117437(G,A); rs6669512(A,G); rs72716185(G,T); rs11161750(G,A); rs1507284(C,T); rs1319648(G,C); rs79295259(C,A); rs6576804(C,T); rs7516054(C,T); rs151320187(C,T); rs80180180(C,G); rs10493783(G,T); rs55740735(G,A); rs78353926(A,G); rs10873756(T,C); rs4912465(C,T); rs1507282(C,T); rs1507283(T,C); rs1414602(C,T); rs1414601(A,C); rs72716190(G,T); rs12727039(G,C); rs12407500(C,T); rs7518215(C,T); rs72716194(A,C); rs12120396(G,A); rs11161752(T,C); rs2892908(T,C); rs114960733(A,G); rs75563006(A,G); rs2135808(C,T); rs12758526(G,C); rs114898859(C,A); rs12130833(A,G); rs12072489(T,C); rs1889851(A,G); rs1889852(T,C); rs9433426(A,G); rs1507277(C,T); rs78989970(G,A); rs6576805(A,C); rs11161754(A,G); rs11161755(A,G); rs11161756(T,C); rs6576806(C,A); rs12072806(G,T); rs11161757(T,G); rs11161758(A,C); rs12074275(G,A); rs11161759(T,C); rs61803679(C,A); rs6660694(T,C); rs4656122(G,C); rs1507276(C,T); rs138592424(T,C); rs72716202(T,G); rs115538928(G,A); rs6697498(T,C); rs4656131(A,T); rs4656132(G,T); rs1999747(C,A)
ccdsGene name	CCDS41353.1
cytoBand name	1p22.3
EntrezGene GeneID	255631
EntrezGene Description	collagen, type XXIV, alpha 1
EntrezGene Type of gene	protein-coding
Annovar Function	COL24A1:NM_152890:exon22:c.C2441A:p.A814D,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.5396
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	Q17RW2
dbNSFP Uniprot ID	COOA1_HUMAN
dbNSFP KGp1 AF	0.0119047619048
dbNSFP KGp1 Afr AF	0.0528455284553
dbNSFP KGp1 Amr AF	0.0
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.0
dbSNP GMAF	0.01194
ESP Afr MAF	0.015616
ESP All MAF	0.00538
ESP Eur/Amr MAF	0.000862
ExAC AF	0.002109

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant;
Autosomal recessive

HEAD AND NECK:
[Eyes];
Progressive cone degeneration (in some patients);
Photophobia;
Nyctalopia;
Decreased central vision;
Dyschromatopsia;
Macular granularity (in some patients);
Central macular atrophy (in some patients);
Central scotoma on Goldmann visual field (in some patients);
Supernormal and delayed scotopic rod electroretinogram (in some patients);
Cone degeneration, stationary (in some patients);
Nystagmus (in some patients);
Normal scotopic responses on rod electroretinogram (in some patients);
Severely reduced cone and absent 30Hz flicker responses on cone electroretinogram
(in some patients)

MISCELLANEOUS:
Onset in first to second decade

MOLECULAR BASIS:
Caused by mutation in the phosphodiesterase 6H, cGMP-specific, cone,
gamma gene (PDE6H, 601190.0001)

OMIM Title
*610025 COLLAGEN, TYPE XXIV, ALPHA-1; COL24A1

OMIM Description

CLONING

By EST database searching, Koch et al. (2003) identified sequences
showing homology to the C-terminal third of alpha-1 type V collagen
(COL5A1; 120215). Using a PCR-based strategy, they cloned a novel human
collagen, designated COL24A1, from a placenta cDNA library. The deduced
protein contains a 38-amino acid signal peptide, followed by a 544-amino
acid N-peptide domain, a 931-amino acid triple helix region with one
imperfect 4-amino acid insertion characteristic of invertebrate
collagens, and a 235-amino acid C-propeptide. The deduced N-peptide
domain contains a thrombospondin N-terminal-like (TSPN) motif that
shares 27.3% sequence identity with the TSPN motifs of COL5A1 and
COL11A1 (120280). Its C-propeptide domain contains 8 cysteines and
shares 28.4% identity with that of COL5A1. The COL24A1 N-peptide
sequence contains a homolog of a conserved sequence characteristic of
fibril diameter-regulating fibrillar collagen chains. COL24A1 is
predicted to have a retained N-peptide after processing. Using RT-PCR of
adult tissues, Koch et al. (2003) demonstrated that mouse Col24a1 is a
nonabundant collagen expressed in bone and retina and to a lesser degree
in cornea, skin, and tendon.

GENE FUNCTION

Using in situ hybridization, Koch et al. (2003) determined that mouse
Col24a1 is first detected in the emerging skeletal elements of the head
and appendicular skeleton at embryonic day 15. Expression at later
embryonic stages was detected in the cornea, the otic capsule, and
skeleton, where expression coincided with the formation of primary
ossification centers and sites of high type I collagen expression. Koch
et al. (2003) concluded that Col24a1 is a marker for embryonic bone
formation and may play a role in regulation of type I collagen
fibrillogenesis.

GENE STRUCTURE

Koch et al. (2003) determined that the COL24A1 gene contains 49 exons.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the COL24A1
gene to chromosome 1 (TMAP SHGC-75097).

GBP3

dbSNP name	rs10922537(A,G); rs12058562(C,A); rs2077694(C,T); rs1409150(T,C); rs11808228(A,G); rs61766155(G,A); rs7550155(C,T); rs7527086(G,A); rs7550252(C,T); rs17433780(A,G); rs10493821(C,T); rs4142706(T,G); rs2390677(A,G); rs113626873(A,G); rs147245917(C,T); rs60788429(C,T); rs72965328(G,A); rs5015501(C,T); rs6659829(T,C); rs141433057(G,A); rs72965332(G,A); rs146670670(G,A); rs77820095(G,T); rs59316955(C,T); rs4656076(C,G); rs113490655(G,A); rs4656077(G,A); rs4656078(C,T); rs12091541(G,A); rs3795543(T,C); rs17130690(G,A); rs45456793(A,G); rs72967452(A,T); rs12089648(A,G); rs12121223(C,T); rs12089694(A,C); rs57846667(T,C); rs10922538(A,G); rs10801702(C,T); rs10922539(G,A); rs141407508(C,T); rs113611878(G,A); rs4655891(C,A); rs10922542(C,T); rs7555039(C,T); rs10922543(T,C); rs7530373(T,G)
ccdsGene name	CCDS717.2
cytoBand name	1p22.2
EntrezGene GeneID	2635
EntrezGene Description	guanylate binding protein 3
EntrezGene Type of gene	protein-coding
Annovar Function	GBP3:NM_018284:exon6:c.C673T:p.R225W,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.6308
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP KGp1 AF	0.322802197802
dbNSFP KGp1 Afr AF	0.164634146341
dbNSFP KGp1 Amr AF	0.342541436464
dbNSFP KGp1 Asn AF	0.281468531469
dbNSFP KGp1 Eur AF	0.447229551451
dbSNP GMAF	0.3228
ESP Afr MAF	0.261008
ESP All MAF	0.388436
ESP Eur/Amr MAF	0.453721
ExAC AF	0.417,8.132e-06

*OMIM Information*

OMIM Clinical Significance
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature

HEAD AND NECK:
[Head];
Macrocephaly, relative;
[Face];
Midface hypoplasia;
Prominent forehead;
Prominent supraorbital ridges;
[Nose];
Depressed nasal bridge (in childhood);
Small, upturned nose (in childhood);
[Teeth];
No abnormalities of teeth

CHEST:
[External features];
Pectus excavatum

SKIN, NAILS, HAIR:
[Skin];
No abnormalities of sweating;
[Nails];
Dysplastic nails (1st and 2nd toes) [Hair];
No abnormalities of hair

MUSCLE, SOFT TISSUE:
Hypotonia

NEUROLOGIC:
[Central nervous system];
Hypotonia;
Developmental delay, primarily motor, resolves in childhood

MISCELLANEOUS:
One family reported (as of May 2012)

OMIM Title
*600413 GUANYLATE-BINDING PROTEIN 3; GBP3

OMIM Description

DESCRIPTION

Guanylate-binding proteins, such as GBP3, are induced by interferon and
hydrolyze GTP to both GDP and GMP (Olszewski et al., 2006).

CLONING

Strehlow et al. (1994) identified and partially characterized a third
member of the GBP family, GBP3, which shows significant sequence
similarity to both GBP1 (600411) and GBP2 (600412).

Olszewski et al. (2006) reported that the 595-amino acid GBP3 protein
shares 88% and 76% identity with GBP1 and GBP2, respectively. All GBPs,
including GBP3, have a conserved N-terminal globular GTP-binding domain
containing 2 consensus sequences and a third T(L/V)RD sequence not found
in other GTPases. GBP3 lacks the C-terminal CaaX isoprenylation motif
found in GBP1, GBP2, and GBP5 (611467). EST database analysis indicated
wide expression of GBP3 in human tissues.

GENE FUNCTION

Using RT-PCR, Tripal et al. (2007) detected high expression of GBP1,
GBP2, and GBP3 in endothelial cells after stimulation with IFNG
(147570), TNF (191160), or IL1B (147720). Immunofluorescence analysis
demonstrated cytoplasmic expression of GBP3.

GENE STRUCTURE

Olszewski et al. (2006) determined that, like other GBPs, the GBP3 gene
contains 11 exons and begins translation in exon 2.

MAPPING

By genomic sequence analysis, Olszewski et al. (2006) mapped the GBP3
gene to the GBP gene cluster on chromosome 1p22.2. It is the most
telomeric GBP gene and is adjacent to GBP1.

LOC729930

dbSNP name	rs623771(T,A)
cytoBand name	1p22.2
EntrezGene GeneID	100421401
EntrezGene Symbol	LOC100421401
snpEff Gene Name	RP4-620F22.3
EntrezGene Description	guanylate binding protein family, member 6 pseudogene
EntrezGene Type of gene	pseudo
Annovar Region type	ncRNA_exonic
snpEff Effect	transcript
snpEff Functional Class	none
snpEff Gene Biotype	processed_pseudogene
snpEff Impact	modifier
dbSNP GMAF	0.3411

GEMIN8P4

dbSNP name	rs2259685(T,C); rs2703984(A,G); rs74548088(A,T); rs7556257(G,A)
cytoBand name	1p22.2
EntrezGene GeneID	492303
snpEff Gene Name	ZNF326
EntrezGene Description	gem (nuclear organelle) associated protein 8 pseudogene 4
EntrezGene Type of gene	pseudo
Annovar Region type	ncRNA_exonic
snpEff Effect	intron
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.06107

SNORA66

dbSNP name	rs115931438(A,G); rs10874744(G,A)
ccdsGene name	CCDS741.1
cytoBand name	1p22.1
EntrezGene GeneID	388650
EntrezGene Symbol	FAM69A
snpEff Gene Name	FAM69A
EntrezGene Description	family with sequence similarity 69, member A
EntrezGene Type of gene	protein-coding
Annovar Region type	ncRNA_exonic
snpEff Effect	downstream
snpEff Functional Class	none
snpEff Gene Biotype	protein_coding
snpEff Impact	modifier
dbSNP GMAF	0.006887
ESP Afr MAF	0.006849
ESP All MAF	0.016393
ESP Eur/Amr MAF	0.020593
ExAC AF	0.017

ABCA4

dbSNP name	rs3747961(T,C); rs76201551(C,T); rs17110718(A,T); rs72956525(C,T); rs12239339(A,G); rs17110724(C,A); rs1932016(G,T); rs72956538(C,T); rs72956540(G,A); rs72956543(A,G); rs115105609(T,C); rs80333611(T,A); rs4147872(G,A); rs6666559(C,G); rs6666652(C,A); rs1800717(A,G); rs12070195(G,C); rs60653897(G,A); rs11806635(C,T); rs17110736(G,A); rs78801978(G,A); rs17110743(G,A); rs10874825(C,T); rs10874826(T,C); rs10874827(C,G); rs6666176(T,G); rs141949394(C,T); rs12083802(C,T); rs78081171(A,G); rs3789374(T,C); rs3789375(T,G); rs11165060(C,T); rs4147871(A,G); rs4147870(G,A); rs4147869(C,T); rs4147868(G,C); rs12070273(A,G); rs12070274(A,T); rs12070278(A,G); rs4147866(T,C); rs1801555(A,G); rs12086793(C,T); rs4147865(G,A); rs4147864(G,A); rs17110761(C,T); rs74102054(T,A); rs17110768(C,T); rs11805625(G,C); rs11805627(G,A); rs115876130(T,C); rs11804211(A,G); rs11804569(A,G); rs74102057(C,T); rs74102058(T,C); rs74102059(A,G); rs74102060(G,A); rs59396776(T,G); rs28422025(T,C); rs4847195(C,T); rs28437464(G,A); rs58541150(A,T); rs12034084(T,A); rs12034085(T,C); rs6541408(T,C); rs35270729(C,A); rs149753560(C,T); rs55691342(C,T); rs7412750(G,A); rs61782235(C,G); rs72956569(G,T); rs11165061(A,G); rs10874829(T,A); rs112487800(C,A); rs113965124(G,A); rs111849559(G,T); rs72956573(A,T); rs7533425(C,G); rs144540817(C,T); rs1762114(A,G); rs4147863(C,T); rs2275028(C,T); rs4147862(C,T); rs145345131(T,G); rs4147861(C,A); rs3789377(G,A); rs557026(T,C); rs3789379(A,G); rs3789380(C,T); rs3789381(C,A); rs3789382(G,A); rs3789383(T,C); rs4147859(G,C); rs4147858(T,C); rs7531001(G,A); rs138873205(T,C); rs3789384(C,T); rs3789385(C,T); rs3789386(A,G); rs145297440(G,T); rs2275029(T,C); rs1800739(C,T); rs2275031(G,T); rs1191234(G,A); rs2275032(A,C); rs4147857(T,C); rs4147856(T,G); rs56166161(G,C); rs55694362(A,G); rs17110808(G,A); rs3789387(T,C); rs76368546(C,G); rs145477946(G,A); rs17110814(C,T); rs2065712(C,T); rs1801574(C,G); rs537831(G,A); rs7519657(C,T); rs2065711(C,T); rs4147855(G,A); rs565155(T,G); rs2893264(C,T); rs61782236(C,T); rs61782237(G,A); rs11165062(G,A); rs11165063(C,G); rs945067(T,C); rs17391542(G,A); rs58088273(T,C); rs12085639(G,A); rs486879(C,T); rs4147853(G,T); rs487906(G,C); rs567370(C,T); rs12082181(T,C); rs114831594(G,T); rs4147851(C,A); rs17391612(G,A); rs3789391(C,T); rs12049183(C,T); rs61782239(C,T); rs12083701(T,A); rs2275033(C,T); rs147187030(A,G); rs56307710(T,C); rs2275034(T,C); rs4147849(T,C); rs914957(T,C); rs914958(A,G); rs72958426(A,G); rs915201(A,G); rs915200(C,T); rs915199(C,T); rs11809593(G,A); rs112385574(A,G); rs11806129(A,G); rs17389488(T,C); rs6664100(G,C); rs6664390(G,A); rs6681968(T,C); rs56031604(T,C); rs17110858(A,G); rs10493867(T,C); rs4147848(G,T); rs933073(T,G); rs472908(G,A); rs12087777(T,C); rs2282229(T,A); rs1932014(G,A); rs55984244(C,T); rs1889407(G,T); rs2151847(A,C); rs115859773(G,A); rs41292681(T,C); rs11165065(G,A); rs111746122(G,A); rs3945204(T,C); rs112707138(C,T); rs17110885(G,T); rs1960277(A,T); rs17110889(C,G); rs17110891(C,G); rs945066(T,G); rs7547334(A,G); rs114846403(G,T); rs4147846(C,T); rs4147845(C,T); rs4147844(G,A); rs547806(T,C); rs2297671(G,A); rs56253197(T,C); rs7543524(G,A); rs4147841(G,A); rs113596322(T,C); rs113011227(C,T); rs11165067(G,A); rs11165068(G,A); rs17389899(A,G); rs375715233(G,A); rs17110905(G,T); rs3789393(T,C); rs12070573(C,T); rs35561994(C,G); rs34541136(T,C); rs11803885(C,A); rs17110916(G,A); rs3789395(A,C); rs1320502(C,T); rs184612341(T,C); rs12087003(A,G); rs1889548(A,C); rs182792816(A,G); rs9661266(T,G); rs11165069(C,T); rs139543506(G,A); rs111809377(A,G); rs140876019(G,A); rs17110922(A,T); rs61749454(A,G); rs17110929(A,T); rs3789398(G,A); rs3789399(G,C); rs4529714(A,G); rs17392369(G,A); rs544830(C,T); rs12123388(C,T); rs4147837(G,A); rs539435(C,G); rs74968378(A,G); rs12095320(A,G); rs12069723(C,G); rs484110(G,A); rs72725167(A,G); rs4147836(C,T); rs77969737(T,C); rs1191231(A,C); rs566927(G,A); rs17110958(A,G); rs497511(G,A); rs1191229(A,G); rs550060(A,G); rs4147835(A,G); rs521538(A,G); rs56197337(A,G); rs4147833(C,T); rs28715983(T,C); rs4847273(A,G); rs6661519(C,A); rs1007348(A,G); rs1007347(T,C); rs72960406(T,C); rs553608(T,C); rs1191232(A,G); rs3789405(T,C); rs149961899(A,G); rs3789406(G,A); rs10493868(A,G); rs3789407(G,C); rs4140392(C,T); rs7366102(T,C); rs1191228(T,C); rs1931575(T,C); rs74102102(G,C); rs2893265(A,G); rs581244(A,T); rs2151849(A,G); rs3789412(C,T); rs149802210(G,C); rs1931574(T,A); rs1334895(T,A); rs12739987(T,C); rs60298190(G,A); rs17110991(C,T); rs182019503(A,G); rs2151848(G,C); rs12759306(C,A); rs1932015(T,C); rs1761375(G,A); rs74104504(A,T); rs556353(A,G); rs4847274(G,C); rs35298667(C,T); rs112095544(G,A); rs524322(A,G); rs17111003(A,G); rs492220(T,C); rs3120133(G,T); rs116450316(C,T); rs4147830(G,A); rs114393289(T,C); rs200943894(C,T); rs2275035(C,T); rs76189878(T,C); rs4147828(A,G); rs4147827(C,G); rs526016(A,G); rs574741(T,C); rs572960(A,G); rs550142(A,G); rs546550(A,G); rs545542(G,C); rs5776202(G,A); rs17461953(A,C); rs515263(A,G); rs479110(T,C); rs481290(T,C); rs560426(C,T); rs563429(A,G); rs1209169(A,G); rs189332620(G,A); rs4847196(G,A); rs10874831(C,T); rs1191238(A,G); rs1191237(A,G); rs554931(T,C); rs483904(T,C); rs66515264(G,T); rs952499(T,C); rs181723030(G,A); rs538880(C,G); rs2068334(G,A); rs76324366(G,C); rs148650711(A,G); rs116079572(G,C); rs4147825(G,A); rs4147823(A,C); rs4147822(A,G); rs4147820(C,T); rs115177659(G,A); rs4847277(T,G); rs184229754(C,T); rs375469791(G,A); rs17100412(C,T); rs77933221(T,C); rs12088309(T,C); rs17111045(G,A); rs140972064(C,T); rs6657239(C,T); rs548122(C,G); rs3789421(G,A); rs3789422(C,T); rs3789423(T,G); rs3789424(G,A); rs577059(T,C); rs72725196(G,A); rs950283(T,C); rs7513438(G,A); rs525749(G,A); rs72960478(T,C); rs2297636(T,C); rs58269697(G,C); rs4147819(G,A); rs481931(G,T); rs571095(G,A); rs3789427(C,G); rs570878(G,T); rs34481412(C,A); rs2184451(G,A); rs1209515(T,C); rs1191236(C,G); rs77597214(C,A); rs11579526(C,T); rs56194707(C,T); rs143259811(C,T); rs75117387(G,A); rs1889406(C,A); rs3789431(C,T); rs79513058(C,A); rs61245991(G,A); rs12057375(G,T); rs4847279(T,C); rs12093963(A,G); rs11165073(C,A); rs4147816(C,T); rs4147815(G,A); rs4147814(C,T); rs4147813(C,A); rs4147812(A,C); rs4147811(C,T); rs3827712(T,C); rs3789432(T,C); rs3789433(A,G); rs115090950(A,C); rs3789434(T,C); rs58902615(T,C); rs3789435(A,G); rs3827713(G,C); rs4147810(A,G); rs2297635(G,A); rs2297634(T,C); rs1889405(C,T); rs1889404(C,T); rs3789438(G,T); rs11165074(G,A); rs12745358(G,A); rs7531875(T,A); rs7524782(C,T); rs7524869(C,A); rs4847281(T,C); rs116306224(G,A); rs4147808(G,A); rs4147807(A,G); rs3789439(T,C); rs3789440(G,A); rs12025221(T,C); rs11805421(C,T); rs10493870(C,T); rs72962308(C,A); rs56127428(T,C); rs10782976(G,A); rs55658984(T,A); rs10747458(C,T); rs3789441(C,T); rs74104526(G,A); rs3789442(G,C); rs3789443(A,G); rs3789444(C,T); rs144564277(C,T); rs7535005(C,T); rs4147805(G,A); rs4147804(G,A); rs3789445(T,G); rs4147803(G,C); rs145618578(A,T); rs11165075(T,C); rs71652552(C,G); rs3789448(G,T); rs57958442(C,T); rs4847282(T,C); rs3827714(G,A); rs11165076(G,T); rs4147802(C,T); rs77357856(C,T); rs4147801(T,C); rs4147800(C,G); rs4147799(A,G); rs11800866(T,C); rs4147798(C,T); rs2184339(T,C); rs114639377(C,T); rs57594899(C,T); rs10782977(T,C); rs113422740(G,A)
ccdsGene name	CCDS747.1
cytoBand name	1p22.1
EntrezGene GeneID	24
EntrezGene Description	ATP-binding cassette, sub-family A (ABC1), member 4
EntrezGene Type of gene	protein-coding
Annovar Function	ABCA4:NM_000350:exon31:c.C4556T:p.T1519M,
Annovar Mutation type	nonsynonymous SNV
Annovar Region type	exonic
dbNSFP LR score	0.5125
snpEff Effect	non_synonymous_coding
snpEff Functional Class	missense
snpEff Gene Biotype	protein_coding
snpEff Impact	moderate
dbNSFP Uniprot Acc	P78363
dbNSFP Uniprot ID	ABCA4_HUMAN
dbNSFP KGp1 AF	0.000457875457875
dbNSFP KGp1 Afr AF	0.0
dbNSFP KGp1 Amr AF	0.0
dbNSFP KGp1 Asn AF	0.0
dbNSFP KGp1 Eur AF	0.00131926121372
dbSNP GMAF	4.591E-4
ESP Afr MAF	0.0
ESP All MAF	7.7e-05
ESP Eur/Amr MAF	0.000116
ExAC AF	7.319e-05

*OMIM Information*

OMIM Clinical Significance

Eyes:
Adult-onset primary open-angle glaucoma (POAG);
Increased intraocular pressure

Inheritance:
Autosomal dominant

OMIM Title
*601691 ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 4; ABCA4
;;ATP-BINDING CASSETTE TRANSPORTER, RETINA-SPECIFIC; ABCR;;
ABC TRANSPORTER, RETINA-SPECIFIC;;
PHOTORECEPTOR RIM PROTEIN; RMP

OMIM Description

DESCRIPTION

The ABCA4 gene produces an ATP-binding cassette (ABC) superfamily
transmembrane protein expressed exclusively in retinal photoreceptors
that is involved in clearance from photoreceptor cells of
all-trans-retinal aldehyde (atRAL), a byproduct of the retinoid cycle of
vision (Sun et al., 1999; Cideciyan et al., 2009).

CLONING

Allikmets et al. (1997) identified the ABCR gene among expressed
sequence tags obtained from human retina. ABCR was found to be closely
related to the mouse and human ABC1 (600046) and ABC2 (600047) genes.
The ABCR gene was not expressed detectably in any of 50 nonretinal fetal
and adult tissues examined. Other studies indicated that the gene is
uniquely retina-specific. The transcript size was estimated to be 8 kb.
Allikmets et al. (1997) reported the complete sequence of the 6,705-bp
ABCR coding region and the predicted 2,235-amino acid polypeptide
encoded by it.

Allikmets et al. (1998) revised the estimate of the size of the ABCR
gene to 6,819 bp encoding a 2,273-amino acid protein.

GENE STRUCTURE

By genomic sequence analysis, Gerber et al. (1998) and Allikmets et al.
(1998) determined that the ABCA4 gene contains at least 50 exons and
spans an estimated 150 kb. Exon sizes range from 33 bp to 266 bp.

MAPPING

Using a whole genome radiation hybrid panel, Allikmets et al. (1997)
mapped the ABCR gene to 1p21-p13, close to microsatellite markers D1S236
and D1S188. They further refined the localization by screening YACs from
the described contig between these anonymous markers. These YACs
delineated a region containing the Stargardt disease gene.

Azarian and Travis (1997) mapped the human photoreceptor rim protein
gene (RMP) to chromosome 1 by radiation hybrid analysis. By homology,
they mapped the mouse Rmp gene to chromosome 3 between the Ly37 and Tshb
loci. Nasonkin et al. (1998) refined the map position of the human ABCR
gene to 1p22.1-p21 by fluorescence in situ hybridization. By contig
mapping, Allikmets et al. (1998) localized the ABCR gene to chromosome
1p22.3-p22.2 between markers D1S3361 and D1S236.

Gross (2014) mapped the ABCA4 gene to chromosome 1p22.1 based on an
alignment of the ABCA4 sequence (GenBank GENBANK AF001945) with the
genomic sequence (GRCh37).

GENE FAMILY

The ATP-binding cassette (ABC) superfamily includes genes whose products
are transmembrane proteins involved in energy-dependent transport of a
wide spectrum of substrates across membranes. Allikmets et al. (1997)
noted that many disease-causing members of this superfamily result in
defects in the transport of specific substrates, e.g., CFTR (602421),
ALD (300100), SUR (600509), PMP70 (170995), and TAP2 (170261). In
eukaryotes, ABC genes typically encode 4 domains that include 2
conserved ATP-binding domains and 2 domains with multiple transmembrane
segments. The ATP-binding domains of the ABC genes contain motifs of
characteristic conserved residues (Walker A and B motifs) spaced by 90
to 120 amino acids. Both this conserved spacing and the 'signature' or
'C' motif just upstream of the Walker B site distinguish members of the
ABC superfamily from other ATP-binding proteins. These features allowed
the isolation of new ABC genes by hybridization, degenerate PCR, and
inspection of DNA sequence databases. Allikmets et al. (1996)
characterized 21 members of the ABC superfamily by determining their map
locations and patterns of expression.

GENE FUNCTION

Allikmets et al. (1997) localized ABCR transcripts exclusively within
photoreceptor cells, indicating that ABCR mediates the transport of an
essential molecule (or ion) either into or out of photoreceptor cells.

The ABCR gene is expressed exclusively in the retina, and in situ
hybridization localized ABCR transcripts to rod photoreceptor cells. Sun
and Nathans (1997) further localized ABCR to the disc membrane of
retinal rod outer segments. The observations narrowed the range of
plausible functions for ABCR and the corresponding range of pathogenic
mechanisms underlying Stargardt disease (STGD; 248200). The authors
commented that the accumulation of lipofuscin in the retinal pigment
epithelium in Stargardt disease might reflect a defective ABCR-mediated
transport of retinoids within the rod outer segment.

Allikmets et al. (1997) commented that the accumulation in the retinal
pigment epithelium (RPE) of a lipofuscin-like substance in STGD suggests
that the site of ABCR-mediated transport may be on the apical face of
the photoreceptor cell and that this transport may affect exchange
between the RPE and the photoreceptors.

To search for natural and artificial substrates and/or allosteric
regulators of ABCR, Sun et al. (1999) solubilized and functionally
reconstituted the purified protein into lipid membranes and surveyed a
group of structurally diverse compounds for their ability to stimulate
or inhibit ABCR ATPase activity. They observed that all-trans-retinal
stimulated the ATPase activity of ABCR 3- to 4-fold. 11-cis- and
13-cis-retinal showed similar activity. All-trans-retinal stimulated the
ATPase activity of ABCR with Michaelis-Menten behavior indicative of
simple noncooperative binding associated with a rate-limiting
enzyme-substrate intermediate in the pathway of ATP hydrolysis. Sun et
al. (1999) concluded that these and other findings supported the
hypothesis that various geometric isomers of retinal and/or other
retinoids are transported by ABCR in a reaction that is coupled to ATP
hydrolysis. The kinetic behavior implied that all-trans-retinal binds to
an intermediate in the ATPase reaction pathway and that this binding
accelerates a rate-limiting step in ATP hydrolysis and/or release of the
hydrolysis products.

Korschen et al. (1999) identified glutamic acid-rich proteins (GARPs;
see 600724) as multivalent proteins that interact with the key players
of cGMP signaling, phosphodiesterase (see 602676) and guanylate cyclase
(see 600179), and with ABCR, through 4 short repetitive sequences. In
electron micrographs, GARPs are restricted to the rim region and
incisures of discs in close proximity to the guanylate cyclase and ABCR,
whereas the phosphodiesterase is randomly distributed. Korschen et al.
(1999) concluded that the GARPs organize a dynamic protein complex near
the disc rim that may control cGMP turnover and possibly other
light-dependent processes.

Molday et al. (2000) showed by immunofluorescence microscopy and Western
blot analysis that ABCR is present in foveal and peripheral cone, as
well as rod, photoreceptors. The results suggested that the loss in
central vision experienced by patients with Stargardt macular dystrophy
arises directly from ABCR-mediated foveal cone degeneration.

The aldehyde group of all-trans-retinal reacts with the primary amine of
phosphatidylethanolamine (PE) to form an equilibrium mixture of
N-retinylidene-PE and all-trans-retinal. Beharry et al. (2004) isolated
Abca4 from bovine rod outer segment disc membranes, and using HPLC and
radiolabeled substrates, they found that Abca4 bound N-retinylidene-PE
and all-trans-retinal. ATP and GTP released these retinoids from Abca4,
but ADP, GDP, and nonhydrolyzable derivatives did not. N-retinyl-PE, the
reduced form of N-retinylidene-PE, also bound Abca4, and
all-trans-retinal bound Abca4 in the absence of PE. All-trans-retinol
did not bind Abca4. Beharry et al. (2004) concluded that ABCA4 functions
as a flippase to translocate N-retinylidene-PE from the lumen to the
cytoplasmic side of retinal disc membranes.

MOLECULAR GENETICS

- Summaries of Mutations

Allikmets (2000) gave a tally of all ABCR alleles as 350 to 400, making
the heterogeneity of ABCR comparable to that of another member of the
ABC superfamily, the cystic fibrosis transmembrane conductance regulator
(CFTR). Allelic variations in ABCR are the most prominent cause of
retinal dystrophies with mendelian inheritance patterns.

Sun et al. (2000) listed 37 reported naturally occurring ABCA4
mutations. By studying expression of ABCR variants in transiently
transfected 293 cells, they observed a wide spectrum of biochemical
defects in these variants and provided insight into the transport
mechanism of ABCR.

- Stargardt Macular Dystrophy

Allikmets et al. (1997) performed mutation analysis of the ABCR gene in
48 families with Stargardt macular dystrophy (STGD1; 248200) previously
ascertained by strict definitional criteria and shown to be linked to
1p. Using a total of 21 exons, they identified 19 different mutations
(see, e.g., 601691.0001-601691.0005), the majority representing missense
mutations in conserved amino acid positions. However, they also found
several 1- to 2-bp insertions and deletions representing frameshifts.
Two missense alterations (D847H; R943Q, 601691.0035) were found in at
least 1 control individual, suggesting that they are neutral
polymorphisms. The remaining mutations were found only in STGD patients
and not in at least 40 unrelated normal controls (80 chromosomes). The
mutations were scattered throughout the coding sequence of the ABCR
gene. Most of the patients were found to be compound heterozygotes but 2
consanguineous families (1 Saudi Arabian (601691.0002) and 1 North
American) were homozygous. In an erratum, Allikmets et al. (1997)
provided a correction of the numbering system for mutations in the ABCR
gene in Stargardt macular dystrophy. Sequencing of ABCR cDNA clones
revealed an additional 114-bp exon after position 4352. This exon adds
38 in-frame amino acids to the polypeptide and represents the major
transcript. See 601691.0004 and 601691.0005.

Nasonkin et al. (1998) reported 4 mutations in the ABCR gene in patients
with Stargardt disease: 3106G-A (601691.0011), 3211insGT (601691.0012),
2565G-A (601691.0013), and 6079C-T (601691.0004).

Lewis et al. (1999) reported results of mutation scanning and direct DNA
sequencing of all 50 exons of ABCR in 150 families segregating autosomal
recessive Stargardt disease (STGD1). ABCR variations were identified in
173 (57%) disease chromosomes, most of which represented missense amino
acid substitutions. These ABCR variants were not found in 220 unaffected
control individuals (440 chromosomes) but did cosegregate with the
disease in these families with STGD1, and many occurred in conserved
functional domains. Missense amino acid substitutions located in the
amino terminal one-third of the protein appeared to be associated with
earlier onset of the disease and may represent misfolding alleles. The 2
most common mutant alleles, gly1961 to glu (601691.0007) and ala1038 to
val (601691.0016), each identified in 16 of 173 disease chromosomes,
represented 18.5% of mutations identified. G1961E in heterozygous state
had previously been associated, at a statistically significant level,
with age-related macular degeneration (ARMD). Clinical evaluation of
these 150 families with STGD1 revealed a high frequency of ARMD in
first- and second-degree relatives. These findings supported the
hypothesis that compound heterozygous ABCR mutations are responsible for
STGD1 and that some ABCR mutations in heterozygous state may enhance
susceptibility to ARMD.

Rivera et al. (2000) studied 144 patients with Stargardt disease and 220
unaffected individuals ascertained from the German population, to
complete a comprehensive, population-specific survey of the sequence
variation in the ABCA4 gene. In addition, they studied 200 individuals
with ARMD to assess the possible role of ABCA4 in that disorder. Using a
screening strategy based primarily on denaturing gradient gel
electrophoresis, they identified a total of 127 unique alterations, of
which 90 had not previously been reported, and classified 72 as probable
pathogenic mutations. Of the 288 Stargardt disease chromosomes studied,
mutations were identified in 166, representing a detection rate of
approximately 58%. Eight different alleles accounted for 61% of the
identified disease alleles, and at least 1 of these, the L541P/A1038V
complex allele (601691.0023), appeared to be a founder mutation in the
German population. When the group with ARMD and the control group were
analyzed with the same methodology, 18 patients with ARMD and 12
controls were found to harbor possible disease-associated alterations.
This represented no significant difference between the 2 groups;
however, for detection of modest effects of rare alleles in complex
diseases, the analysis of larger cohorts of patients may be required.

Yatsenko et al. (2001) tested the hypothesis that patients with
late-onset Stargardt disease, i.e., onset at 35 years or later, retained
partial ABCR activity attributable to mild missense alleles. They
approached this study by in vivo functional analysis of various
combinations of mutant alleles. They directly sequenced the entire
coding region of ABCR and detected mutations in 33 of 50 (66%) disease
chromosomes, but surprisingly, 11 of 33 (33%) were truncating alleles.
Importantly, all 22 missense mutations were located outside the known
functional domains of ABCR (ATP-binding or transmembrane), whereas in
the general cohort of STGD1 subjects studied by Lewis et al. (1999),
alterations occurred with equal frequency across the entire protein.
Yatsenko et al. (2001) suggested that these missense mutations in
regions of unknown function are milder alleles and are more susceptible
to modifier effects. Thus, they corroborated a prediction from the model
of ABCR pathogenicity that (1) one mutant ABCR allele is always missense
in late-onset STGD1 patients, and (2) the age of onset is correlated
with the amount of ABCR activity of this allele. In addition, they
reported 3 new pseudodominant families, bringing the total to 8 of 178
outbred STGD1 families, and suggested a carrier frequency of
STGD1-associated ABCR mutations of about 4.5% (approximately 1 in 22).

Using double gradient-denaturing gradient gel electrophoresis (DG-DGGE),
Fumagalli et al. (2001) performed a mutation screen in 44 Italian
autosomal recessive Stargardt disease patients corresponding to 36
independent genomes. In 34 of the 36 patients (94.4%), 37 sequence
changes were identified, including 26 missense, 6 frameshift, 3
splicing, and 2 nonsense variations. Twenty of the 37 mutations had not
previously been described. There appeared to exist a subset of molecular
defects specific to the Italian population. The identification of at
least 2 disease-associated mutations in 4 healthy control individuals
indicated a higher than expected carrier frequency of variant ABCR
alleles in the general population. Genotype-phenotype analysis showed a
possible correlation between the nature and location of some mutations
and specific ophthalmoscopic features of STGD disease.

Fingert et al. (2006) reported a case of Stargardt disease in a patient
homozygous for a mutation in the ABCA4 gene (601691.0026) as a result of
uniparental isodisomy of chromosome 1. The patient's father was
heterozygous for the mutation.

Pal Singh et al. (2006) identified homozygous null mutations in the
ABCA4 gene (601691.0028-601691.0029) in affected members of 2 Indian
families with early-onset severe retinal dystrophy.

- Age-Related Macular Degeneration

Age-related macular degeneration (ARMD; see 153800) is the leading cause
of severe central visual impairment among the elderly and is associated
both with environmental factors such as smoking and with genetic
factors. Allikmets et al. (1997) screened 167 unrelated ARMD patients
for alterations in the ABCR gene. Thirteen different ARMD-associated
alterations, both deletions and amino acid substitutions (e.g.,
601691.0006), were found in 1 allele of ABCR in 26 patients (16%). The
authors suggested that identification of ABCR alterations will permit
presymptomatic testing for high-risk individuals and may lead to earlier
diagnosis of ARMD and to new strategies for prevention and therapy.

De La Paz et al. (1999) screened their patients with ARMD (159 familial
cases from 112 multiple families and 53 sporadic cases) and 56 racially
matched individuals with no known history of ARMD for evidence of
mutation in the ABCR gene. The authors identified only 2 of the
previously reported variants in their study population. Both variants
occurred in sporadic cases, and none was found in familial cases or in
the randomly selected population. In addition, the authors identified
several previously undescribed polymorphisms and variants in both the
ARMD and control populations. The authors concluded that mutation in the
ABCR gene is not a major genetic risk factor for ARMD in their study
population.

Shroyer et al. (1999) analyzed the ABCA4 gene in a 3-generation family
manifesting both Stargardt disease and ARMD, and identified
heterozygosity for a missense mutation (P1380L; 601691.0026) in the
paternal grandmother with ARMD, whereas the proband and his 2 paternal
cousins with Stargardt disease were compound heterozygous for the P1380L
mutation and another missense mutation (601691.0036 and 601691.0037,
respectively) in the ABCA4 gene. Shroyer et al. (1999) suggested that
carrier relatives of STGD patients may have an increased risk of
developing ARMD.

Allikmets and the International ABCR Screening Consortium (2000) tested
the original hypothesis that ABCR is a dominant susceptibility locus for
ARMD by screening 1,218 unrelated ARMD patients of North American and
western European origin and 1,258 comparison individuals from 15 centers
in North America and Europe for the 2 most frequent ARMD-associated
variants found in ABCR: G1961E (601691.0007) and D2177N (601691.0006).
One or the other of these sequence changes was found in 1 allele of ABCR
in 40 patients (3.4%) and in 13 control subjects (0.95%). These
differences were considered statistically significant. The risk of ARMD
was elevated approximately 3-fold in D2177N carriers and approximately
5-fold in G1961E carriers.

By mutation analysis in a cohort of families that manifested both STGD
and ARMD, Shroyer et al. (2001) found that ARMD-affected relatives of
STGD patients are more likely to be carriers of pathogenic STGD alleles
than predicted based on chance alone. Shroyer et al. (2001) used an in
vitro biochemical assay to test for protein expression and ATP-binding
defects, and found that mutations associated with ARMD have a range of
assayable defects ranging from no detectable defect to apparent null
alleles. Of the 21 missense ABCR mutations reported in patients with
ARMD, 16 (76%) showed abnormalities in protein expression, ATP binding,
or ATPase activity. They inferred that carrier relatives of STGD
patients are predisposed to develop ARMD.

Guymer et al. (2001) investigated the role of the G1961E (601691.0007)
and D2177N (601691.0006) alleles of the ABCA4 gene in the pathogenesis
of ARMD. They concluded that although the ABCA4 gene is definitively
involved in the pathogenesis of Stargardt disease and some cases of
photoreceptor degeneration, the alleles did not appear to be involved in
a statistically significant fraction of ARMD cases.

Single-copy variants of the ABCR gene have been shown to confer enhanced
susceptibility to ARMD. Bernstein et al. (2002) examined 19 of 33 sibs
from 15 Stargardt families who carried their respective proband's
variant ABCR allele. Some families exhibited concordance of ABCR alleles
with the macular degeneration phenotype, but others did not. Exudative
ARMD was uncommon among both probands and sibs.

- Retinitis Pigmentosa 19

Martinez-Mir et al. (1998) demonstrated that the causative mutation in a
family with retinitis pigmentosa-19 (601718) was a frameshift
(601691.0008) in the ABCR gene, which was present in homozygous state.
The authors observed that the heterozygous parents, aged 72 and 82, in
their family showed no signs of age-related macular dystrophy (ARMD).
They thought, however, that this finding did not argue against
haploinsufficiency of ABCR as the cause of ARMD; because this is a
multifactorial disorder, ABCR haploinsufficiency may be only a
predisposing factor, and not all parents of patients have ARMD. ABCR
expression is confined to rods, and the fact that these photoreceptors
are the cell type primarily affected in RP support ABCR as the gene
responsible for RP19. They pointed out that the highest concentration of
rods is 5 mm out from the fovea, within the zone that is affected in
macular degeneration. If the rods in Stargardt disease and age-related
macular degeneration produce an aberrant product, it would be expected
to reach its highest concentration in this region. Persons with 1
wildtype and 1 mutant ABCR allele would be predisposed to a late-onset
accumulation of cellular debris (drusen) and the development of ARMD.

- Cone-Rod Dystrophy 3

To evaluate the importance of the ABCA4 gene as a cause of autosomal
recessive cone-rod dystrophy (CORD3; 604116), Maugeri et al. (2000)
studied 5 patients with autosomal recessive CORD and 15 patients with
isolated CORD, all from Germany and the Netherlands. They found 19 ABCA4
mutations in 13 (65%) of 20 patients. In 6 patients, mutations were
identified in both ABCA4 alleles; in 7 patients, mutations were detected
in 1 allele. The complex ABCA4 allele L541P/A1038V (601691.0023) was
found exclusively in German patients with CORD; 1 patient carried this
complex allele in homozygous state, and 5 others were compound
heterozygous.

Following the studies of Maugeri et al. (2000), Ducroq et al. (2002)
evaluated the prevalence of ABCA4 mutations in a cohort of 55 patients
with autosomal recessive or sporadic cone-rod dystrophy. They screened
the 50 exons of the ABCA4 gene as well as the flanking intronic
sequences using DHPLC and identified 16 different mutant alleles in 13
(23.6%) of 55 patients. Among these 13 patients, 2 were homozygotes
(from 2 consanguineous families; see, e.g., 601691.0024), 4 were
compound heterozygotes, and 7 were simple heterozygotes. There was no
significant difference in the frequency of ABCA4 mutations between
autosomal recessive and sporadic cases of CORD (6 of 29 versus 7 of 26
cases, respectively). Ducroq et al. (2002) estimated that this screen
detected approximately 80% of mutations present in these families, with
unidentified mutations potentially located in promoter or intron
sequences or in undiscovered exons, and stated that the corrected
mutation frequency would then be 29.5% of all CORD cases. For a sporadic
case of cone-rod dystrophy with no ABCA4 mutation, they estimated that
the risk of the disease being inherited as an autosomal recessive
condition can be estimated to be 15.6% using the Bayesian calculation.

Fishman et al. (2003) examined 30 patients with autosomal recessive
CORD, 16 of whom harbored plausible disease-causing variations in the
ABCA4 gene. Among the mutation-positive patients, 2 distinctly different
fundus phenotypes were observed: 12 showed diffuse pigmentary
degenerative changes (type 1), whereas 4 showed either no pigmentary
changes or only a mild degree of peripheral pigment degeneration (type
2). All 16 patients showed either a central scotoma (6 patients) or both
a central scotoma and some degree of peripheral field loss (10
patients). Both cone and rod a- and b-wave electroretinogram (ERG)
amplitudes were reduced in all patients, which is diagnostic for CORD.
Of the 12 patients classified as type 1, 4 harbored an A1038V change
(601691.0016): in 2 this was the only sequence variation identified; in
1 case, it was observed in compound heterozygosity with a nonsense
mutation; and in 1 case it was found as a complex allele with an L541P
mutation (see 601691.0023). In the additional 8 patients classified as
type 1, 2 showed 2 different heterozygous missense mutations, 3 had a
single heterozygous missense mutation, and 3 had a heterozygous splice
site mutation within intron 40 (601691.0010). In the 4 patients with
considerably less funduscopically apparent pigmentary change (type 2), a
heterozygous missense mutation was observed: in 2 instances L1201R
(601691.0025), and in another 2 L2027F (601691.0004).

Ducroq et al. (2006) analyzed a large multiplex Christian Arab family
with presumed autosomal recessive CORD and 6 consanguineous loops and
found segregation of 3 distinct haplotypes at the CORD3 locus.
Sequencing of the ABCA4 gene revealed 3 different mutations segregating
with the disease in this family: 4 patients were homozygous for a splice
site mutation; 4 were compound heterozygous for the splice site mutation
and 1 of 2 missense mutations, respectively; and 1 patient was compound
heterozygous for the 2 missense mutations. Ducroq et al. (2006)
emphasized the pitfalls of homozygosity mapping in highly inbred
families when the heterozygote carrier frequency is high in the general
population.

Kitiratschky et al. (2008) screened the ABCA4 gene in 64 patients with
cone or cone-rod dystrophy and a family history consistent with
autosomal recessive inheritance. They identified mutations in 20 (31%)
of 64 patients, including 16 with CORD and 3 with cone dystrophy (see,
e.g., 601690.0007, 601690.0010, and 601691.0030-601691.0033).

- Susceptibility to Cleft Lip/Palate

For a discussion of a possible association between variation in the
ABCA4 gene and susceptibility to nonsyndromic cleft lip/palate, see
119530.

GENOTYPE/PHENOTYPE CORRELATIONS

Stargardt disease and late-onset fundus flavimaculatus (FFM) are
autosomal recessive disorders leading to macular degeneration in
childhood and adulthood, respectively. Rozet et al. (1998) screened the
entire coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM
families and showed that mutations truncating the ABCR protein
consistently led to STGD. On the other hand, all mutations identified in
FFM were missense mutations affecting uncharged amino acids. They stated
that this was the first genotype/phenotype correlation in ABCR gene
mutations.

Shroyer et al. (1999) reviewed ABCR mutations and the associated retinal
diseases and proposed a model in which ABCR activity inversely
correlates with severity of disease. In this model, truncating and
severely misfolding mutations are associated with early-onset disease
characterized by a primary photoreceptor loss and secondary retinal
pigment epithelium (RPE) defects (retinitis pigmentosa and cone-rod
dystrophy). In patients with milder mutations, photoreceptors are spared
initially, but byproducts of faulty ABCR transport lead to accumulated
material in the RPE and sequential photoreceptor loss (Stargardt disease
and fundus flavimaculatus). Similarly, ABCR-associated ARMD might be due
to the gradual accumulation of these same byproducts with eventual
photoreceptor loss.

Klevering et al. (2004) described 3 Dutch families in which different
combinations of retinal disorders occurred: ARMD, RP, and STGD in the
first family, RP and STGD in the second family, and ARMD, CORD, and STGD
in the third family. Three different mutations in the ABCA4 gene were
identified in these families. In view of the relatively high carrier
frequency of ABCA4 mutations (approximately 5%) in the general
population, Klevering et al. (2004) concluded that the occurrence of
various combinations of relatively rare retinal disorders in one family
might not be as uncommon as once believed.

Wiszniewski et al. (2005) analyzed missense mutations (see, e.g.,
601691.0023) in the photoreceptors of transgenic Xenopus laevis tadpoles
and found mislocalization of ABCA4 protein. These mutations caused
retention of ABCA4 in the photoreceptor inner segment, likely by
impairing correct folding, resulting in the total absence of physiologic
protein function. Patients with different retinal dystrophies harboring
2 misfolding alleles exhibit early age of onset (5 to 12 years) of
retinal disease. Wiszniewski et al. (2005) suggested that a class of
ABCA4 mutants may be an important determinant of the age of onset of
retinal disease.

Valverde et al. (2007) screened for mutations in the ABCA4 gene in 60
patients in 50 Spanish families with different retinal dystrophies: 16
with autosomal recessive CORD, 27 with autosomal recessive retinitis
pigmentosa, and 7 with autosomal dominant macular degeneration. Sixteen
distinct variants were identified in 25 of the families. Thirteen of the
CORD families had mutations in the ABCA4 gene; the most prevalent
mutation in these families was a 2888delG mutation (601691.0027),
accounting for 30% of the alleles detected. Putative disease-associated
alleles were identified in 9 of the RP families and in 3 of the macular
degeneration families.

In 66 individuals with known disease-causing ABCA4 alleles, Cideciyan et
al. (2009) defined retina-wide disease expression by measuring rod and
cone photoreceptor-mediated vision. Serial measurements over a mean
period of 8.7 years were consistent with a model wherein a normal
plateau phase of variable length was followed by initiation of
retina-wide disease that progressed exponentially. Estimates of the age
of disease initiation were used as a severity metric and contributions
made by each ABCA4 allele were predicted. One-third of the nontruncating
alleles were found to cause more severe disease than premature
terminations, supporting the existence of a pathogenic component beyond
simple loss of function.

ANIMAL MODEL

By SDS-PAGE and immunoblot analysis of purified bovine and frog rod
outer segments, Azarian and Travis (1997) identified 210- and 240-kD
proteins, respectively, as RMP. By peptide microsequence analysis and
degenerate primers for nested PCR on bovine and mouse retinal libraries,
Azarian and Travis (1997) isolated a mouse Rmp cDNA encoding a putative
2,310-amino acid protein. Sequence analysis predicted 86% identity and
92% similarity of mouse RMP to human ABCR protein, 3 potential
N-glycosylation sites, 12 membrane-spanning segments, 2 ABC transporter
signature motifs with potential phosphorylation sites, and 2 consensus
ATP/GTP nucleotide-binding sites. Northern blot analysis revealed
expression exclusively in retina. Immunoblot analysis showed that RMP is
expressed predominantly in the outer segments of retinal photoreceptors.

Weng et al. (1999) characterized the ocular phenotype in Abcr knockout
mice. Mice lacking the Abcr gene showed delayed dark adaptation,
increased all-trans-retinaldehyde (all-trans-RAL) following light
exposure, elevated phosphatidylethanolamine (PE) in outer segments,
accumulation of the protonated Schiff base complex of all-trans-RAL and
PE (N-retinylidene-PE), and striking deposition of a major lipofuscin
fluorophore (A2E) in retinal pigment epithelium (RPE). These data
suggested that ABCR functions as an outwardly directed flippase for
N-retinylidene-PE. Delayed dark adaptation is likely due to accumulation
in discs of the noncovalent complex between opsin and all-trans-RAL.
ABCR-mediated retinal degeneration in patients may result from
'poisoning' of the RPE due to A2E accumulation, with secondary
photoreceptor degeneration due to loss of the ABCR support role.

The primary pathologic defect in Stargardt disease is accumulation of
toxic lipofuscin pigments, such A2E, in cells of the RPE. This
accumulation was thought to be responsible for the photoreceptor death
and severe visual loss in patients with Stargardt disease. Sieving et
al. (2001) found that treatment of rodents with isotretinoin (Accutane),
an agent used in the treatment of acne, delayed rhodopsin regeneration
and slowed recovery of rod sensitivity after light exposure.
Importantly, isotretinoin did not cause photoreceptor degeneration and
actually protected photoreceptors from light-induced damage. Light
activation of rhodopsin results in its release of
all-trans-retinaldehyde, which constitutes the first reactant in A2E
biosynthesis. A side effect of treatment with isotretinoin is reduced
night vision because of its inhibitory effect on 11-cis-retinol
dehydrogenase (601617) in RPE cells. Radu et al. (2003) tested the
effects of isotretinoin on lipofuscin accumulation in Abcr knockout
mice, a model of recessive Stargardt disease. They observed by electron
microscopy that isotretinoin blocked the formation of A2E biochemically
and the accumulation of lipofuscin pigments. No significant visual loss
was observed in Abcr-null mice by electroretinography. Isotretinoin also
blocked the slower, age-dependent accumulation of lipofuscin in wildtype
mice. The results suggested that treatment with isotretinoin may inhibit
lipofuscin accumulation and delay the onset of visual loss in patients
with Stargardt disease and may be an effective treatment for other forms
of retinal or macular degeneration associated with lipofuscin
accumulation.